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Information on EC 3.4.21.79 - granzyme B and Organism(s) Homo sapiens and UniProt Accession P10144
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- 3.4.21.79
- perforin
- t-cells
- cd8
-
cytolytic
-
immunotherapy
- vaccine
- lymphoma
-
rejection
- tnf
- dendritic
-
cell-mediated
- ifn-gamma
-
allograft
-
tregs
- tia-1
- fasl
- foxp3
-
autologous
- interferon-gamma
-
caspases
-
degranulation
-
allogeneic
-
epstein-barr
-
antigen-specific
-
virus-specific
-
immunophenotype
-
ctla-4
-
anti-cd3
-
tumor-infiltrating
-
nk-cell
-
extranodal
-
elispot
- synthesis
-
eomes
-
graft-versus-leukemia
-
cd45ro
-
alcls
- biotechnology
-
death-1
- analysis
-
intragraft
- lag-3
-
hiv-specific
- medicine
- diagnostics
- degradation
-
alloreactive
-
lymphocyte-mediated
-
lymphokine-activated
- crma
-
b-mediated
- pharmacology
-
ag-specific
-
banff
-
hepatosplenic
-
anti-pd-1
- interleukin-15
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
granzyme b, gra-b, asp-ase, lymphocyte protease, gzm b, pro-apoptotic serine protease, granzyme g, ctla1, progrb, cytotoxic cell proteinase-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
GrB
-
C11
-
-
-
-
CCP1
-
-
-
-
CCPII
-
-
-
-
CTLA1
-
-
-
-
CTSGL1
-
-
-
-
Cytotoxic cell proteinase-1
-
-
-
-
granzyme B
-
-
Granzyme G
-
-
-
-
Granzyme H
GrB
-
-
HLp
-
-
-
-
Human lymphocyte protein
-
-
-
-
Lymphocyte protease
-
-
-
-
Proteinase, CCP1
-
-
-
-
SECT
-
-
-
-
T-cell serine protease 1-3E
-
-
-
-
Granzyme H
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
143180-74-9
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-IEPD-4-nitroanilide + H2O
acetyl-IEPD + 4-nitroaniline
an asp-ase substrate, high activity
-
-
?
acetyl-VEID-4-nitroanilide + H2O
acetyl-VEID + 4-nitroaniline
an asp-ase substrate, low activity
-
-
?
2-aminobenzoyl-IEPDSSMESK-dinitrophenyl + H2O
?
-
susbtrate is specific for human GrB
-
-
?
Ace-Ile-Glu-Pro-Asp-p-nitroanilide + H2O
Ace-Ile-Glu-Pro-Asp + p-nitroaniline
-
-
-
-
?
acetyl-DEVD-7-amido-4-methylcoumarin + H2O
?
-
efficient cleavage by GzmB after K562 cells are exposed to sublytic perforin or streptolysin O. GzmH shows only baseline readings
-
-
?
acetyl-IETD-7-amido-4-methylcoumarin + H2O
acetyl-IETD + 7-amino-4-methylcoumarin
-
-
-
-
?
acetylcholine receptor
?
-
granzyme B efficiently and specifically cleaves alpha and epsilon subunits of acetylcholine receptor, especially the epsilon subunit
-
-
?
acetylcholine receptor + H2O
?
-
extracellular GrB substrate. Implication: cleavage results in a reduction of the receptor in neuromuscular junctions and yields an autoantigenic fragment
-
-
?
adenovirus DNA-binding protein + H2O
?
-
gzmB and gzmH. Direct cleavage of DNA-binding protein by gzmH is a critical component of the cytotoxic antiviral response against adenovirus, which slows down DNA viral replication. Cleaved by gzmH at multiple sites, most efficient cleavage at Met118, when this site is mutated, gzmH instead cleaves at Phe121
-
-
?
aggrecan + H2O
?
-
extracellular GrB substrate. Implication: Disruption of structural integrity in cartilage
-
-
?
AHNAK + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: calcium signalling, associated disease: systemic lupus erythematosus
-
-
?
alanyl tRNA synthetase + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis
-
-
?
alpha-fodrin + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: cytoskeletal protein, associated disease: Sjörgen's syndrome
-
-
?
alpha-tubulin + H2O
truncated alpha-tubulin
-
alpha-tubulin derived from HeLa S100 extracts or Jurkat S100 extracts is cleaved by grB in a caspase-independent manner. Cleavage occurs at D438. Polymerized and soluble alpha-tubulin can be cleaved
-
-
?
ATSY-7-amido-4-methylcoumarin + H2O
ATSY + 7-amino-4-methylcoumarin
-
GzmH
-
-
?
Bcl-2-associated athano gene-1 + H2O
?
-
GrB proteolysis is independent of caspase activity
-
-
?
BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 + H2O
?
-
generated with similar efficiency by mouse and human recombinant granzyme B
-
-
?
beta-actin + H2O
?
-
GrB cleavage fragments of beta-actin are detected in medullary carcinoma of the breast tumor lysates, suggesting that CTL-mediated death of medullary carcinoma of the breast tumor cells and actin redistribution may have a function in the generation of autoimmunity to beta-actin
-
-
?
cartilage proteoglycans + H2O
?
-
extracellular GrB substrate. Implication: Disruption of structural integrity in cartilage
-
-
?
caspase-8 + H2O
?
-
cleaves human caspase-8 but fails to cleave the mouse counterpart of caspase-8. Mouse caspase-8 is processed only upon addition of cytochrome c and dATP to J774 extracts to activate the apoptosome pathway to caspase activation
-
-
?
centromere protein B + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Scleroderma
-
-
?
centromere protein C + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Scleroderma
-
-
?
chromodomain helicase DNA binding 4 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: gene expression, associated disease: myositis
-
-
?
DNA binding protein + H2O
?
-
granzyme B and granzyme H (cleavage at Met118 and Phe121)
-
-
?
DNA-PK catalytic subunit + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA repair, associated disease: myositis
-
-
?
FGFR1 + H2O
?
-
extracellular GrB substrate. Implication: cleavage activates pro-cell death functions as well as inactivates pro-growth signals
-
-
?
glutamate receptor subunit 3 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: Glutamate receptor, associated disease: Rasmussen's encephalitis
-
-
?
hepatitis antigen lamin B + H2O
?
-
cleavage of autoimmune hepatitis antigen lamin B by GrA and B causes disruption of the nuclear lamina, by uncoupling lamin B from its nuclear localisation signal
-
-
?
histidyl tRNA synthetase + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis
-
-
?
Hsc70/Hsp70-interacting protein + H2O
?
-
Hsc70/Hsp70-interacting protein is cleaved at both GrB cleavage sites (at sequences IEPD92-TD and INPD180-SA) during NK-mediated cell death in a caspase-independent manner. Hsc70/Hsp70-interacting protein is a substrate unique to GrB
-
-
?
Hsp90 + H2O
?
-
is proteolyzed at multiple sites by GrB. Cleavage at sequences IDED693-EV and INPD631-PI in Hsp90beta. Cleavage at sequences IDED701-DP, INPD639-HS and VRTD175-TG in Hsp90alpha
-
-
?
human endogenous retrovirus K-10 gag + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: endogenous retrovirus, associated disease: systemic lupus erythematosus
-
-
?
ICAD + H2O
?
-
cleaves human ICAD but fails to cleave the mouse counterpart
-
-
?
inhibitor of caspase-activated DNase + H2O
caspase-activated DNase
-
cleaved in a dose-dependent fashion
-
-
?
interleukin IL-1alpha + H2O
?
-
cleavage after the motif IAND103, no substrate for caspases -1, -3, -4, -5, and -7
granzyme B-mediated processing of IL-1alpha potently enhances the biological activity
-
?
interleukin proIL-18 + H2O
interleukin IL-18 + ?
-
-
cleavage at residues D35-Y36 of proIL-18, identical to cleavage site of caspase-1
-
?
Ki-67 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: proliferation, associated disease: myositis
-
-
?
Ku-70 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA repair, associated disease: myositis
-
-
?
La protein + H2O
?
-
La is cleaved by gzmB and gzmH. La is a direct target of gzmH during cytotoxic-mediated cell death. Cleavage of La by gzmH occurs at Phe-364 (P(1) site) and generates a COOH-terminal truncated form of La that loses nuclear localization and decreases hepatitis C virus-internal ribosome entry site-mediated translational activity
-
-
?
Laminin + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, anoikis
-
-
?
LEADKGKLEYD + H2O
LEAD + KGKLEYD
-
is a far better substrate for mouse granzyme B as compared with human granzyme B
-
-
?
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Met thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl ester + H2O
?
-
-
-
-
?
neuronal glutamate receptor + H2O
?
-
extracellular GrB substrate. Implication: GrB cleaves the non-glycosylated form of the receptor into an autoantigenic fragment
-
-
?
nuclear mitotic apparatus protein 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Sjörgen's syndrome
-
-
?
nucleolus organizing region 90 kDa (NOR-90/UBF) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription factor, associated disease: Scleroderma
-
-
?
nucleophosmin (B23) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: rRNA processing, associated disease: Scleroderma
-
-
?
nucleophosmin + H2O
?
-
efficiently cleaves nucleophosmin of human origin, does not cleave nucleophosmin within J774 cell free extracts
-
-
?
PEG-P + H2O
?
-
virtually all soluble PEG-P is cleaved in 3 min, suggesting PEG-P is a sensitive indicator of granzyme B activity. The granzyme can not access PEG-P when encapsulated in 1,2-dioleoyl-sn-glycero-3-phosphocholine large unilamellar vesicles
-
-
?
plasmin + H2O
?
-
extracellular GrB substrate. Implication: as plasmin is pro-angiogenic, cleavage results in the reduction of angiogenesis
-
-
?
plasminogen + H2O
?
-
extracellular GrB substrate. Implication: cleavage yields angiostatin, which is anti-angiogenic. Implications in angiogenesis
-
-
?
PMScl/EXOSC10 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mRNA degradation, associated disease: myositis/Scleroderma
-
-
?
poly(ADP)ribose polymerase 1 (PARP1) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: ribosylation, associated disease: systemic lupus erythematosus
-
-
?
polypyrimidine tract-binding protein + H2O
?
-
2times more efficiently cleaved by mouse versus human recombinant granzyme B
-
-
?
postmeiotic segregation 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA mismatch repair, associated disease: myositis
-
-
?
postmeiotic segregation 2 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA mismatch repair, associated disease: myositis
-
-
?
pro-caspase-7 + H2O
?
-
activates caspase-7, whether of human or murine origin, with a similar efficiency
-
-
?
Protease CMH-1 + H2O
?
-
a close homologue of CPP32, granzyme B specifically cleaves at Asp198-Ser199 between the p20 and p12 and activates the cysteine protease
-
-
?
PTSY-7-amido-4-methylcoumarin + H2O
PTSY + 7-amino-4-methylcoumarin
-
GzmH
-
-
?
pyruvate dehydrogenase complex E2 (PDC-E2) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: acetyl CoA synthesis, associated disease: primary biliary cirrhosis
-
-
?
RNA polymerase I + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
RNA polymerase II + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
signal recognition particle 72 kDa + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis, systemic lupus erythematosus
-
-
?
smooth muscle cell matrix + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, anoikis
-
-
?
topoisomerase 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
transaldolase + H2O
?
-
specifically cleaved by human GrB. The recognition site is a VVAD motif at aa residue 27
the major C-terminal GrB cleavage product of transaldolase, residues 28-337, has no enzymatic activity but retains the antigenicity of full-length transaldolase, effectively stimulating the proliferation and cytotoxic lymphocyte activity of peripheral blood mononuclear cells and of CD8+ T cell lines from patients with multiple sclerosis. Sera of multiple sclerosis patients exhibit similar binding affinity to wild-type and GrB-cleaved transaldolase
-
?
U1 small nuclear ribonucleoprotein 70 kDa + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: RNA processing, associated disease: systemic lupus erythematosus, Scleroderma, myositis
-
-
?
ubiquitin fusion degradation 2 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: ubiquitination, associated disease: Scleroderma
-
-
?
beta-glycan + H2O
?
100 kDa protein, cleavage by the enzyme into fragments of about 60 kDa and 40 kDa
-
-
?
biglycan + H2O
?
40 kDa protein, cleavage by the enzyme into fragments of about 30 kDa and 20 kDa
-
-
?
ClpX unfoldase + H2O
?
Escherichia coli N-terminal GST-tagged 37kDa ClpX. Human GzmB is predicted to cut ClpX after Asp144, in the AAA domain and interfere with its unfolding activity
-
-
?
decorin + H2O
?
65 kDa protein, cleavage by the enzyme into fragments of about 50 kDa and 30 kDa
-
-
?
BID + H2O
truncated BID + ?
-
both human and mouse BID are cleaved efficiently
-
-
?
BID + H2O
truncated BID + ?
-
efficient cleavage of mouse and human Bid by human granzyme B
-
-
?
DNA-PKcs + H2O
?
-
directly and efficiently cleaved in vitro and in vivo, abolishes kinase activity
-
?
DNA-PKcs + H2O
?
-
directly and efficiently cleaved in vitro and in vivo, abolishes kinase activity
-
?
fibrillarin + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: rRNA processing, associated disease: Scleroderma
-
-
?
Fibrinogen + H2O
?
-
granzyme B is unable to cleave soluble fibrinogen, granzyme B cleaves the matrix form at several sites
-
-
?
Fibrinogen + H2O
?
-
extracellular GrB substrate. Implication: matrix form of fibrinogen is cleaved. The uncleaved protein is responsible for platelet adhesion and thrombus growth. Cleavage results in anti-thrombosis implications
-
-
?
Fibronectin + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, migration, and anoikis
-
-
?
Notch1 + H2O
?
-
extracellular GrB substrate. Implication: cleavage results in cell signaling affecting tumor survival and antiviral activities
-
-
?
Notch1 + H2O
?
-
transmembrane receptor, Notch1 is a direct and caspase-independent substrate. GrB cleaves the intracellular Notch1 domain at least twice, at residues D1860 and D1961. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. GrB also displays perforin-independent functions by cleaving the extracellular domain of Notch1
cleavage of Notch1 by GrB results in a loss of transcriptional activity, independent of Notch1 activation. GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
-
GrB cleaves PAD4 exclusively at D388
-
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
-
PAD4, is cleaved by GrB at a single site, aspartic acid 388 (D388). Dynamic changes occur in the PAD4 structure induced by GrB cleavage. Recombinant N-terminal 6xHis tagged PAD4 (NP_036519) is expressed and purified from Escherichia coli BL21(DE3)pLysS competent cells
-
-
?
pro-caspase-3 + H2O
?
-
activates caspase-3, whether of human or murine origin, with a similar efficiency
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
-
cleaves human pro-caspase-3 generating a 21-kDa and a 17-kDa fragment (autocatalytic removal of the caspase-3 prodomain)
-
-
?
Protease CPP32 + H2O
?
-
CPP32 is the precursor of the protease responsible for cleavage of poly(ADPribose)polymerase
-
-
?
Protease CPP32 + H2O
?
-
granzyme B activates CPP32, which is now able to bind inhibitors and cleave the substrate poly(ADPribose)polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli
-
-
?
Vitronectin + H2O
?
-
Grb expressed in human bladder cancer cell lines 1512 and RT112 cleave vitronectin
-
-
?
Vitronectin + H2O
?
-
extracellular GrB substrate. Implication: GrB cleavage site in integrin-binding domain, implications in cell adhesion, migration, and anoikis
-
-
?
von Willebrand factor + H2O
?
-
granzyme B delays ristocetin-induced platelet aggregation and inhibits platelet adhesion and spreading on immobilized von Willebrand factor under static conditions. In vitro, granzyme B cannot cleave the von Willebrand factor conformer in solution, but cleavage is induced when von Willebrand factor is artificially unfolded or presented as a matrix. Granzyme B cleaves von Willebrand factor with comparable efficiency to proteinase ADAMTS-13 and rapidly processes ultra-large von Willebrand factor multimers released from activated endothelial cells under physiological shear. Granzyme B cleaves the A1 and A3 domains of von Willebrand factor
-
-
?
von Willebrand factor + H2O
?
-
extracellular GrB substrate. Implication: GrB cleavage site in the domain of platelet interaction, prevention/delay of thrombosis
-
-
?
additional information
?
-
the enzyme cleaves exracellular matrix proteins, release of active TGF-beta1
-
-
?
additional information
?
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
granzyme B (GzmB) is an asp-ase. Granzyme B is a hematopoietic serine protease, which cleaves after negatively charged amino acids. Cleavage specificity analysis using chromogenic and recombinant substrates. Comparisons of GzmB consensus sequences, overview
-
-
?
additional information
?
-
-
granzyme B (GzmB) is an asp-ase. Granzyme B is a hematopoietic serine protease, which cleaves after negatively charged amino acids. Cleavage specificity analysis using chromogenic and recombinant substrates. Comparisons of GzmB consensus sequences, overview
-
-
?
additional information
?
-
human GzmB cleaves only two of the three asp-ase substrates (no activity with acetyl-YVAD-4-nitroanilide) and not the chymase substrate succinyl-AAPF-4-nitroanilide or the two elastase substrates, succinyl-AAPV-4-nitroanilide and succinyl-AAPA-4-nitroanilide. This indicates a broader specificity against different asp-ase substrates for the opossum GzmB compared to human GzmB. Also no activity of the oppossum GznB with N-(tert-butoxycarbonyl)-VLGR-4-nitroanilide (a tryptase substrate), N-benzyloxycarbonyl-GPR-4-nitroanilide (a tryptase substrate), succinyl-AAPI-4-nitroanilide (an elastase substrate), succinyl-AAPL-4-nitroanilide, and succinyl-LLVY-4-nitroanilide (a chymase substrate). Both opossum and human GzmB prefer the rat GzmB consensus sequence. The rat GzmB consensus sequence contains two negatively charged amino acids in the P1 and P3 positions of the substrate. The cleavage of these substrates results in two clearly separated smaller bands, indicating cleavage only at one site in the middle of the linker sequence. Human GzmB cleaves the human substrate sequence (LIGAD-VLVQ) almost as efficiently as the rat GzmB consensus (LIETD-SGL)
-
-
?
additional information
?
-
-
human GzmB cleaves only two of the three asp-ase substrates (no activity with acetyl-YVAD-4-nitroanilide) and not the chymase substrate succinyl-AAPF-4-nitroanilide or the two elastase substrates, succinyl-AAPV-4-nitroanilide and succinyl-AAPA-4-nitroanilide. This indicates a broader specificity against different asp-ase substrates for the opossum GzmB compared to human GzmB. Also no activity of the oppossum GznB with N-(tert-butoxycarbonyl)-VLGR-4-nitroanilide (a tryptase substrate), N-benzyloxycarbonyl-GPR-4-nitroanilide (a tryptase substrate), succinyl-AAPI-4-nitroanilide (an elastase substrate), succinyl-AAPL-4-nitroanilide, and succinyl-LLVY-4-nitroanilide (a chymase substrate). Both opossum and human GzmB prefer the rat GzmB consensus sequence. The rat GzmB consensus sequence contains two negatively charged amino acids in the P1 and P3 positions of the substrate. The cleavage of these substrates results in two clearly separated smaller bands, indicating cleavage only at one site in the middle of the linker sequence. Human GzmB cleaves the human substrate sequence (LIGAD-VLVQ) almost as efficiently as the rat GzmB consensus (LIETD-SGL)
-
-
?
additional information
?
-
no activity with Escherichia coli ClpB protein
-
-
?
additional information
?
-
-
no activity with Escherichia coli ClpB protein
-
-
?
additional information
?
-
-
preference for substrates with Glu or Asp as the residue amino-terminal to the scissile bond, little or no activity with oligopeptide substrates for trypsin-like, chymotrypsin-like, and elastase-like proteases
-
-
?
additional information
?
-
-
preference for substrates with Glu or Asp as the residue amino-terminal to the scissile bond, little or no activity with oligopeptide substrates for trypsin-like, chymotrypsin-like, and elastase-like proteases
-
-
?
additional information
?
-
-
induces DNA degradation and apoptosis of cells
-
?
additional information
?
-
-
requirement for aspartic acid in the substrate P1 position
-
?
additional information
?
-
-
requirement for aspartic acid in the substrate P1 position
-
?
additional information
?
-
-
plays an essential role in cytotoxic T-lymphocyte-mediated cell killing
-
-
?
additional information
?
-
-
the enzyme cleaves and activates CPP32, the precursor of the protease responsible for cleavage of poly(ADPribose)polymerase
-
-
?
additional information
?
-
-
participates in target cell death inflicted by cytotoxic lymphocytes
-
-
?
additional information
?
-
-
induces apoptosis of abnormal cells by cleaving intracellular proteins
-
?
additional information
?
-
-
protects the organism against intracellular infections and cellular transformation, implicated in the generation of tissue damage in a variety of chronic conditions, including autoimmunity and transplant rejection
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis <6>
-
?
additional information
?
-
-
after prolonged incubation, enzyme causes pronounced morphological changes in human tumor cells, leading to partial loss of contact to the culture support
-
-
?
additional information
?
-
-
compared with granzyme B, granzyme A is minor effector of target cell lysis by natural killer cells
-
-
?
additional information
?
-
-
caspases 2, 3 and 7 (C285A mutants) and purified BID are not directly cleaved by GzmH. No activity of GzmH toward Ac-LEHD-7-amino-4-methylcouramin
-
-
?
additional information
?
-
-
granzyme H does not cleave BID or inhibitor of caspase-activated death, does not activate caspases
-
-
?
additional information
?
-
-
granzyme B does not bind membrane phospholipids nor has intrinsic membranolytic properties
-
-
?
additional information
?
-
-
granzyme B has no effect on platelet adhesion and spreading on immobilized collagen. Granzyme B does not cleave glycocalicin (extracellular domain of GPIbalpha)
-
-
?
additional information
?
-
-
mediates cleavage at Asn36 (neo-N terminus: LALLEEIEAENR) in the mouse and at Asp37 (neo-N terminus: LALMEEMEAEHR) in the human DNA polymerase delta catalytic subunit
-
-
?
additional information
?
-
-
tetrapeptide substrate specificity of human GrB: In addition to the requirement for aspartic acid in the P1 position, P4 is specific for Ile, Val, and Leu, whereas P3 and P2 are able to accommodate a wider range of amino acids
-
-
?
additional information
?
-
-
the GrB cleavage sites defined within autoantigens reveal several features: first, all have Ile, Leu, or Val in P4 and are cleaved after the P1 aspartic acid. Second, amino acids in the P2 and P3 positions in autoantigens are almost universally favored by human GrB, but not tolerated by caspases (e.g. proline in P2)
-
-
?
additional information
?
-
-
many autoantigens are substrates for the protease granzyme B
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
interleukin IL-1alpha + H2O
?
-
cleavage after the motif IAND103, no substrate for caspases -1, -3, -4, -5, and -7
granzyme B-mediated processing of IL-1alpha potently enhances the biological activity
-
?
interleukin proIL-18 + H2O
interleukin IL-18 + ?
-
-
cleavage at residues D35-Y36 of proIL-18, identical to cleavage site of caspase-1
-
?
Notch1 + H2O
?
-
transmembrane receptor, Notch1 is a direct and caspase-independent substrate. GrB cleaves the intracellular Notch1 domain at least twice, at residues D1860 and D1961. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. GrB also displays perforin-independent functions by cleaving the extracellular domain of Notch1
cleavage of Notch1 by GrB results in a loss of transcriptional activity, independent of Notch1 activation. GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
-
GrB cleaves PAD4 exclusively at D388
-
-
?
transaldolase + H2O
?
-
specifically cleaved by human GrB. The recognition site is a VVAD motif at aa residue 27
the major C-terminal GrB cleavage product of transaldolase, residues 28-337, has no enzymatic activity but retains the antigenicity of full-length transaldolase, effectively stimulating the proliferation and cytotoxic lymphocyte activity of peripheral blood mononuclear cells and of CD8+ T cell lines from patients with multiple sclerosis. Sera of multiple sclerosis patients exhibit similar binding affinity to wild-type and GrB-cleaved transaldolase
-
?
Vitronectin + H2O
?
-
Grb expressed in human bladder cancer cell lines 1512 and RT112 cleave vitronectin
-
-
?
DNA-PKcs + H2O
?
-
directly and efficiently cleaved in vitro and in vivo, abolishes kinase activity
-
?
additional information
?
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
-
plays an essential role in cytotoxic T-lymphocyte-mediated cell killing
-
-
?
additional information
?
-
-
the enzyme cleaves and activates CPP32, the precursor of the protease responsible for cleavage of poly(ADPribose)polymerase
-
-
?
additional information
?
-
-
participates in target cell death inflicted by cytotoxic lymphocytes
-
-
?
additional information
?
-
-
induces apoptosis of abnormal cells by cleaving intracellular proteins
-
?
additional information
?
-
-
protects the organism against intracellular infections and cellular transformation, implicated in the generation of tissue damage in a variety of chronic conditions, including autoimmunity and transplant rejection
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis <6>
-
?
additional information
?
-
-
after prolonged incubation, enzyme causes pronounced morphological changes in human tumor cells, leading to partial loss of contact to the culture support
-
-
?
additional information
?
-
-
compared with granzyme B, granzyme A is minor effector of target cell lysis by natural killer cells
-
-
?
additional information
?
-
-
many autoantigens are substrates for the protease granzyme B
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CaCl2
-
50 mM, enhances Nalpha-tert-butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl esterase activity
NaCl
-
0.1-1.0 M, highest activity with Nalpha-tert-butyloxycarbonyl-Ala-Ala-Met thiobenzyl ester
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S,5S)-4-oxo-5-[[N-(phenylacetyl)-L-isoleucyl]amino]-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
(2S,5S)-5-[(N-acetyl-L-isoleucyl)amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
(2S,5S)-5-[[N-(1-benzothiophen-3-ylacetyl)-L-isoleucyl]amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
(3R)-N-cyclopropyl-1-(3-[[(3-methoxyphenyl)sulfonyl]amino]benzoyl)piperidine-3-carboxamide
-
(3S)-N-cycloheptyl-3-methyl-1-oxo-2-(pyridin-2-ylmethyl)-10-(1H-pyrrol-1-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide
-
(5R)-4-(3-methoxybenzyl)-10-methyl-N-(3-methylbutyl)-3-oxo-3,4,5,5a,10,10a-hexahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide
-
2-[(4E)-4-[3-methoxy-4-(prop-2-yn-1-yloxy)benzylidene]-2,5-dioxoimidazolidin-1-yl]-N-(4-methylphenyl)acetamide
-
2-[(5E)-5-[4-(2-amino-2-oxoethoxy)-3-methoxybenzylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(3,4-dimethylphenyl)acetamide
-
3-(4-chlorophenyl)-2-([[5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-yl]sulfanyl]methyl)quinazolin-4(3H)-one
-
engineered chimeric human antichymotrypsin
engineering of a extracellular GrB serpin: a chimeric protein is generated in which the reactive center loop (RCL) of human extracellular antichymotrypsin (ACT) is replaced with that of serpina3n, a mouse extracellular inhibitor of GrB lacking in humans. This serpin contains 27 amino acid residues from the serpina3n RCL and the remaining 395 residues from human ACT. The insertion converts human ACT into a GrB-inhibitory serpin. Several critical residues are identified by scanning mutagenesis on the chimera and serpina3n. Targeted mutagenesis is conducted on wild-type human ACT by specifically substituting those critical residues, creating an inhibitor that contains 99.3% human ACT sequence with only three point mutations. Inhibition kinetics
-
hydroxy(6-[2-methoxy-4-[(E)-(3-[2-[(4-methylphenyl)amino]-2-oxoethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]pyridin-3-yl)oxoammonium
-
IEPD-CHO
a tetrapeptide aldehyde inhibitor, binding structure analysis from crystal structure, PDB ID 1IAU
N-acetyl-L-isoleucyl-L-alpha-glutamyl-N-[(2S)-1-carboxy-3-oxopropan-2-yl]-L-prolinamide
-
serine protease inhibitor A3N
i.e. serpin A3N or SA3N, an extracellular inhibitor of GrB possessing multiple biological functions, including the attenuaxadtion of muscular dystrophy in mice, neuropathic pain, and GrB-mediated decorin cleavage and rupture. It also induces neuroprotection in vitro and in vivo. Role of GrB inhibitor SA3N on Escherichia coli LPS-induced inflammation in NK-92 cells. SA3N pretreatment prevents the LPS-induced changes in expression levels of GRP78, CHOP, NF-kappaB, and IkappaBalpha proteins. Also SA3N pretreatment prevents the expression and exocytosis of GrB by LPS
-
(2S,5S)-N-((1H-1,2,3-triazol-4-yl)methyl)-5-((3S,4S)-3-(2-(benzo[b]thiophen-3-yl)acetamido)-4-methyl-2-oxohexylamino)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
specific granzyme B inhibitor
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
100K assembly protein of human adenovirus type 5
-
potent and specific inhibitor
-
adenovirus 100K assembly protein
-
inhibits gzmB, gzmH relieves gzmB inhibition
-
benzyloxycarbonyl-Ala-Ala-Asp-chloromethylketone
-
GrB-specific inhibitor. Addition completely blocks reaction with interleukin proIL-18
Bio-x-IEPDp-(Oph)2
-
specific and irreversible inhibition both in vitro and in cells
interleukin-10
-
granzyme B release from both alloreactive cytotoxic T cell clones and an Epstein-Barr virus-specific cytotoxic T cell clone is inhibited in the presence of interleukin-10 serum
-
interleukin-4
-
significantly suppresses granzyme B synthesis. Interleukin-4-mediated suppression of granzyme B leads to impaired cytotoxicity of adaptive regulatory T cells against K562 target cells
-
L4-100k assembly protein
-
acts as a sink that binds to and inhibits granzyme B, preventing target cell death
-
PI-9
-
granzyme B forms a specific SDS-stable complex with its cognate inhibitor, PI-9
-
serpin inhibitor PI-9
-
granzyme B specific serpin inhibitor, complexation of enzyme with inhibitor prevents recognition by receptor importin beta and eliminates requirement of importin alpha for nuclear import
-
serpina3n
-
inhibitor for human and mouse GrB, expressed by Sertoli cells. Inhibitor shares homology with human alpha-1-anti-chymotrypsin
-
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
-
-
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
-
GzmB inhibitor
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
-
peptide-mimetic analog of IEPD-aldehyde
additional information
structure-based design of non-covalent small molecule inhibitors for human granzyme B via virtual screening strategy employing three constraints and probe sitemapping with FTMAP, usage of crystal structure PDB ID 1FQ3
-
additional information
-
structure-based design of non-covalent small molecule inhibitors for human granzyme B via virtual screening strategy employing three constraints and probe sitemapping with FTMAP, usage of crystal structure PDB ID 1FQ3
-
additional information
-
inhibition of caspases does not clonogenically rescue cells from human GzmB
-
additional information
-
natural killer cells stimulated in vitro with interleukin-2 reduce their granzyme H levels over 3-4 days
-
additional information
-
treatment of T1 cells with pifithrin-alpha results in inhibition of p53 phosphorylation and in a significant decrease in GrB-induced apoptotic T1 cell death. siRNA targeting p53 induces inhibition of streptolysin-O/GrB-mediated apoptotic T1 cell death
-
additional information
-
zVAD-fmk completely inhibits GzmB induced executioner caspase activity
-
additional information
-
back salt progressively inhibits granzyme B-mediated von Willebrand factor cleavage
-
additional information
-
induced hypoacetylation in GZMB gene loci by a HAT inhibitor (curcumin) results in decreased expressions of GZMB in memory cells in response to in vitro stimulation
-
additional information
-
no significant difference of granzyme B between patients without immunologic treatment and patients after introduction of immunologic treatment, this may be attributed to the variety of clinical stage at the introduction of immunologic treatment and the variety of immunologic treatment
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
A23187
-
induces granzyme B expression in mast cell lines HMC-1 and LAD2 and cord blood-derived mast cells
compound 48/80
-
induces granzyme B expression in mast cell line LAD2 and cord blood-derived mast cells
Substance P
-
induces granzyme B expression in mast cell line LAD2 and cord blood-derived mast cells
additional information
-
CMV/EBV/influenza peptide pool peptides do not induce GzB release in CD8+ cells from healthy donors within 24 h. Purified CD8+ cells after CMV/EBV/influenza peptide pool peptide stimulation show induction of GzB after 72 h in vitro. HIV peptides induce GzB secretion in HIV-infected individuals directly ex vivo
-
additional information
-
GzB is not induced in purified CD8+ cells by CEF peptides ex vivo. Low frequencies of GzB producing CD8+ cells after mitogen stimulation. IFN-gamma positive, GzB negative CD8+ memory cells convert into GzB producing cells within 2 days after antigen stimulation. Induction of GzB producing CD8+ cells after Vaccinia virus booster immunization. HIV peptides induce GzB production in HIV-infected individuals directly ex vivo
-
additional information
-
mature skin-derived mast cells only produce granzyme B upon IgE-dependent stimulation by FcepsilonRI
-
additional information
-
natural killer cells stimulated in vitro with interleukin-2 express progressively greater amounts of perforin and granzyme B
-
additional information
-
no GzB activity in CTL or NK92 effector cells, but activity rapidly becomes detectable throughout the target cytoplasm after effector-target engagement. Lack of GzB activity in Jurkat cells following intrinsic and extrinsic apoptotic stimuli
-
additional information
-
activation of CD4+ T cells with anti-CD3 and anti-CD28 or anti-CD46 induces granzyme B expression in all cells. Granzyme B expression in anti-CD3/anti-CD46 activated CD4+ T cells is much higher than granzyme B expression induced by usual activation (anti-CD3/anti-CD28)
-
additional information
-
granzyme B level is elevated in the early stage of Rasmussen syndrome around the onset of epilepsy and remains slightly elevated even in the progressed stage, and declines within a few months to more or less constant levels
-
additional information
-
in the presence of perforin, modest cleavage of the encapsulated PEG-P at large unilamellar vesicles/perforin molar ratio of 1000 at acidic and neutral pH. Granzyme B requires a translocation agent to enter the target cell. Granzyme B readily accesses PEG-P only when a membrane disrupting agent, e.g. TX-100, streptolysin O or perforin, is present
-
additional information
-
in vitro stimulation increases the mRNA levels of GZMB in both naive and memory cells. Activation-induced GZMB expression increases significantly faster and higher in memory cells than in naive cells for the first 24-32 h. At 72 h after stimulation, naive cells express higher levels of GZMB than do memory cells
-
additional information
-
plasma level of granzyme B increases significantly by day 14, with a peak at day 7 after onset of acute myocardial infarction. Significant positive correlation between the plasma granzyme B level on day 14 and the increase in left ventricular end-diastolic volume index over 6 months after acute myocardial infarction
-
additional information
-
ristocetin does not increase granzyme B cleavage in the presence or absence of salt
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.013
(2S,5S)-4-oxo-5-[[N-(phenylacetyl)-L-isoleucyl]amino]-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
pH 7.4, 30°C
0.038
(2S,5S)-5-[(N-acetyl-L-isoleucyl)amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
pH 7.4, 30°C
0.000007
(2S,5S)-5-[[N-(1-benzothiophen-3-ylacetyl)-L-isoleucyl]amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
pH 7.4, 30°C
0.08
N-acetyl-L-isoleucyl-L-alpha-glutamyl-N-[(2S)-1-carboxy-3-oxopropan-2-yl]-L-prolinamide
pH 7.4, 30°C
0.000008
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.045
(3R)-N-cyclopropyl-1-(3-[[(3-methoxyphenyl)sulfonyl]amino]benzoyl)piperidine-3-carboxamide
Homo sapiens
pH 7.4, 30°C
0.044
2-[(4E)-4-[3-methoxy-4-(prop-2-yn-1-yloxy)benzylidene]-2,5-dioxoimidazolidin-1-yl]-N-(4-methylphenyl)acetamide
Homo sapiens
pH 7.4, 30°C
0.025
2-[(5E)-5-[4-(2-amino-2-oxoethoxy)-3-methoxybenzylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(3,4-dimethylphenyl)acetamide
Homo sapiens
pH 7.4, 30°C
0.044
3-(4-chlorophenyl)-2-([[5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-yl]sulfanyl]methyl)quinazolin-4(3H)-one
Homo sapiens
pH 7.4, 30°C
0.035
5-[2-(4-chlorophenoxy)ethoxy]-1-cyclohexyl-1H-tetrazole
Homo sapiens
pH 7.4, 30°C
0.028
hydroxy(6-[2-methoxy-4-[(E)-(3-[2-[(4-methylphenyl)amino]-2-oxoethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]pyridin-3-yl)oxoammonium
Homo sapiens
pH 7.4, 30°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7 - 7.5
-
Nalpha-tert-butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl ester
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 8.5
-
pH 6: about 60% of activity maximum, pH 8.5: about 45% of activity maximum
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
B19, HBoV1 and Candida albicans antigens are all found to induce peripheral blood mononuclear cell (PBMC) to secrete GrB in 30 parvovirus B19-seropositive and 22 parvovirus B19-seronegative subjects
-
Epstein-Barr virus-transformed autologous B lymphoblastoid cell line
-
IL-21 and GzmB serum levels are highly correlated in subjects with systemic lupus erythematosus and freshly isolated CD51 systemic lupus erythematosus B cells constitutively express GzmB
-
granzyme B mRNA expression is increased 2.9fold in a severe septic human subject
-
in stroke samples, Gra-b co-localizes with Annexin-V+/TUNEL+ in degenerating neurons
-
cytotoxic lymphocyte subsets and T regulatory cells, most circulating CD56+8- NK cells and half of circulating CD8+ T lymphocytes coexpress both granzymes A and B. Activation of CD8+ T-lymphocytes with concanavalin A and of CD4+ T-lymphocytes with antibodies to CD3/CD28 or CD3/CD46 induces substantial expression of granzyme B, but not of granzyme A. Granzyme B-expressing CD4+ Tr1 cells are capable of killing target cells in a perforin-dependent manner
-
in medullary carcinoma of the breast (MCB), GrB-expressing cytotoxic T cells are found in large numbers, often nearby apoptotic tumor cells
-
regulatory T cells (Tregs) freshly isolated from the peripheral blood of normal adults lack granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, express high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone fail to induce granzyme B. Treatment of Tregs with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppressed granzyme B expression
-
expressed in the synovial fluid of rheumatoid arthritis patients
-
levels of GrB in the serum and synovial fluid of rheumatoid arthritis patients is strikingly associated with the severity of erosive joint disease
-
GrB is expressed, in absence of perforin in urothelial carcinoma cells. Significant differences are found between GrB expression and both increasing pathological tumor spreading and high-grade vs. low-grade pTa tumors
additional information
GrB expressing cells are increased in hemophagocytic lymphohistiocytosis, enzyme expression is decreased following immunosuppressive therapy
cytotoxic, interleukin-6 induces CD4 T cells to express the enzyme
elevated granzyme B in cytotoxic T lymphocytes. The cells only express granzyme B following stimulation and differentiation into cytotoxic T lymphocytes. CD8 expressing GrB cells are increased in hemophagocytic lymphohistiocytosis, regardless of genetic etiology
-
expressed in the bronchoalveolar lavage of patients with chronic obstructive pulmonary disease and lung inflammation
-
granzyme B expression is increased in lung transplant patients
-
expressed in the cerebrospinal fluid of multiple sclerosis and Rasmussen encephalitis patients
-
of activated CTL lines, grown in the presence of recombinant interleukin 2
-
a proportion of granzyme B is constitutively secreted by cytotoxic T lymphocytes in the absence of target cell engagement. Cytotoxic T lymphocyte primarily secrete inactive granzyme B zymogen, bypassing the granules. They produce less granzyme B than natural killer cells, but secrete much more (58%) than they store
-
cord blood- and mature skin-derived mast cells. Majority of lesional mast cells express abundant GrB
-
express high levels of granzyme H but relatively low levels of granzyme B
-
only the YT cell line, which is a poor killer expresses low levels of GzmH
-
a proportion of granzyme B is constitutively secreted by natural killer cells in the absence of target cell engagement. The protease is primarily released in an active form through secretory granules except in YT cells that mainly release inactive granzyme B zymogen. A-NK and NK92 cells secrete a comparatively small proportion of their granzyme B (ca. 10 and 0.3% of the total per hour, respectively), whereas YT cells release about 29%
-
natural killer cells expressing CD16, generally express gA, gB and perforin simultaneously
-
cells that do not express either granzyme (gA- or gB-) rarely express perforin and generally express little or no CD57. Granzyme B is never expressed without granzyme A. gA- gB- cells can only express low levels of perforin, as high perforin content requires expression of gA and gB. Less differentiated, naive T cells express no cytotoxic enzymes (gA- gB- Perf-), and nearly all highly differentiated effector T cells (which are largely terminally differentiated CD57 bright cells) express the three cytotoxic enzymes simultaneously. The majority of CMV-specific T cells express gA, gB, and perforin, whereas EBV-specific T cells mostly express gA but not gB and HIV-specific T cells express gA, gB but low levels of perforin
-
levels of GrB in the serum and synovial fluid of rheumatoid arthritis patients is strikingly associated with the severity of erosive joint disease
-
low levels of granzyme B mRNA within non-lesional skin, significant increase in granzyme B expression within lichen planus lesions. Positive correlation between levels of mRNA of granzyme B and granulysin within lesions of lichen planus
-
granzyme B is present in thymus glands from myasthenia patients, but is absent in thymus from normal adult subjects
-
granzyme B and its substrate acetylcholin receptor epsilon subunit are aberrantly expressed in thymus from patients with Myasthenia gravis
additional information
following binding to Hsp70, GrB is rapidly internalized into tumor cells
additional information
granzyme B (GrB) belongs to a family of serine proteases that are expressed in the granules of activated CTLs and NK cells that induce apoptosis. GrB is also expressed in non-lymphoid lineage cells, including chondrocytes, neutroxadphils, keratinocytes, and macrophages
additional information
-
increased protein levels in all regions of vessels with advanced atherosclerosis, i.e., superficial intima, deep intima, and the media. In the intima granzyme B is present within lipid-rich regions in which it localizes to TUNEL-positive foam cells of atherosclerotic plaques. In allograft vasculopathy increase of protein levels only in the deep intima
additional information
-
neither monocytes nor activated CD8+ CTLs show any GzmH expression
additional information
-
no GzB activity in CTL or NK92 effector cells. Lack of GzB activity in Jurkat cells
additional information
-
unstimulted HMC-1 cells and LAD 2 cells show no Grb mRNA and protein, expression upon stimulation with non-physiological stimuli
additional information
-
alphabeta T cell and gammabeta T cell express gA, gB and perforin simultaneously
additional information
-
CD4+ adaptive regulatory T cells generated by co-ligation of CD3 and CD46 express high amounts of granzyme B
additional information
-
granzyme B is not detectable in K562 cell-conditioned medium
additional information
-
low levels of GZMB mRNA and no detectable levels of granzyme B protein in resting naive or memory CD8 T cells
additional information
-
large airway brushing: granzyme B expression is increased in lung transplant patients
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
both perforin and GzmB are endocytosed into giant endosomal antigen-1 endosomes that form after perforin treatment
-
for nuclear import, receptor importin alpha is required, while receptor importin beta inhibits import
additional information
-
GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus
-
-
cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells
-
cytoplasmic granules of cytotoxic T lymphocytes anf natural killer cells
-
rapid uptake of external enzyme by HeLa cells and accumulation in cytoplasm in inactive form, uptake does not depend on enzyme activity or on mannose 6-phosphate receptor
-
active in cytoplasmic granules, mainly located in the dense core, partially colocalizes with tryptase in granules with both lysosomal and secretory features
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
the identification of a granzyme B homologue with aspase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. An asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus. The mast cell chymase and GzmB were the first two enzymes to appear in this locus. Granzyme B is the only member of the hematopoietic serine proteases, which cleaves after negatively charged amino acids. Phylogenetic analysis and tree, overview
malfunction
physiological function
malfunction
-
inhibition or downregulation of GrB suppresses bladder cancer cell invasion in vitro
physiological function
additional information
-
effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4, overview
malfunction
Tresp cells from patients with multiple sclerosis resist Treg suppression via a mechanism that involves GzmB
malfunction
increased circulating granzyme B in type 2 diabetes patients with low-grade systemic inflammation, correlated with unfavorable inflammatory profile, as described by elevated levels of validated adipokines such as interleukin-6, TNF-alpha, and WISP1. Multivariate linear regression analysis shows that increased GrB is associated with type 2 diabetes diagnosis independently from possible confounders
malfunction
inhibition of granzyme B activity blocks inflammation induced by lipopolysaccharide through regulation of endoplasmic reticulum stress signaling in NK92 cells. Inhibition of GrB activity suppresses the changes of NF-kappaB and IkappaBalpha expression levels induced by LPS as part of endoplasmic reticulum stress
physiological function
in contrast to the intracellular GzmB that mediates apoptosis, GzmB can be found in extracellular fluids where it is hypothesized to regulate other cellular processes. GzmB-induced apoptosis involves the granule-mediated delivery of GzmB into the cytoplasm of target cells. Extracellular enzyme strongly inhibits Treg suppression, without altering Treg viability, nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell suppression by HLA-DR-CD25hiCD127lo tregs in multiple sclerosis and in response to interleukin-6. The suppression-abrogating cytokine interleukin-6 augments GzmB expression by human CD4 T cells, and it inhibits Treg suppression via this nonapoptotic GzmB-mediated mechanism. DR2CD127lo Tregs stimulated in the presence of extracellular GzmB exhibit reduced expression of the suppression-associated molecules CD39 and PD-L1
physiological function
natural killer cells exhibit cell killing activity that primarily mediated by the pro-apoptotic serine protease granzyme B, which enters targets cells with the help of the pore-forming protein perforin
physiological function
pathogenic extracellular role for GrB in cardiovascular disease, during inflammation, the enzyme accumulates in the extracellular space, retains its activity, and is capable of cleaving extracellular matrix proteins
physiological function
the recombinant and native enzyme directly inhibits the growth of human laryngeal cancer Hep-2 cells in vitro and in vivo, respectively
physiological function
Asp-ase activity of the Opossum granzyme B supports the role of granzyme B as part of anti-viral immunity
physiological function
cytotoxic CD4+ cells have a part in controlling chronic viral infections such as EBV, CMV and HIV, they secrete granzyme B and perforin after pathogen induction. Direct cytotoxicity of parvovirus B19-specific CD4+ cells versus GrB secretion among seven parvovirus B19-seropositive subjects, overview. Pathogenetic role of these B19-specific CD4+ T cells secreting GrB (and possibly IL-17) in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
physiological function
granzyme B (GrB) is a serine protease produced by some leukocytes, including cytotoxic lymphocytes and macrophages, that exerts both intracellular apoptotic function and extracellular functions, leading to tissue injury, inflammation and repair. Role for GrB in the pathogenesis of several chronic inflammatory diseases
physiological function
granzyme B (GrB) is a serine protease that is expressed in the lytic granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), it plays a role in target cell apopxadtosis and a non-cytotoxic role in inflammation
physiological function
granzyme B (GrB) is the initiator of multiple pro-apoptotic pathways and serves as the principle cytotoxic molecule deployed by T cells and natural killer (NK) cells to eliminate target cells. Endogenous GrB is produced as a zymogen bearing an N-terminal Gly-Glu dipeptide that prevents the formation of a functional catalytic triad. Upon packaging into lytic granules inside the immune cell, GrB is processed by the dipeptidyl peptidase cathepsin C (CatC), which cleaves off GrB's Gly-Glu dipeptide and frees the newly N-terminal Ile16 residue to insert into the interior of the molecule and form a salt bridge with Asp194. The resulting conformational change enables the simultaneous generation of an oxyanion hole and maturation of the active-site S1 pocket. Since endogenous GrB is activated prior to its release from the lytic granules of T cells and NK cells, it indiscriminately kills any target cell it enters and does not independently ascertain the identity of the target cell. Target-cell identification is established exclusively at the cell surface via receptor-antigen interactions
physiological function
granzyme B acts against schizont-stage Plasmodium falciparum with IC50 of 0.00159 mM
physiological function
granzyme B disrupts central metabolism and protein synthesis in bacteria to promote an immune cell death program. Granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. Because killer cells use a multi-pronged strategy to target vital pathways, bacteria may not easily become resistant to killer cell attack. The cytotoxic granule pore-forming protein, perforin (PFN), delivers the death-inducing granzyme (Gzm) serine proteases into the target cell, where they cleave multiple substrates to kill the target cell. These cytotoxic cells also kill intracellular bacteria and protozoa. Granzymes A and B (Gzms A and B), the most abundant of the five human Gzms, rapidly trigger oxidative bacterial death by cleaving and disrupting electron transport chain complex I (ETC I), which generates toxic superoxide anions. At the same time, the Gzms degrade bacterial oxidative defense enzymes to disrupt the ability of bacteria to survive oxidative stress. GzmB cleavage of Clp system proteins disrupts the Clp function of removing proteins targeted for degradation
physiological function
intracellular role of Granzyme B (GrB) in immune-mediated cell killing. Enzyme GrB is also implicated in extracellular pathways of inflammation, cytokine activation and autoimmunity
physiological function
the serine protease granzyme B (GrB) is produced as an effector molecule and is activated by T and natural killer cells, it specifically targets membrane-bound 70 kDa heat shock protein (mHsp70) on tumor cells, i.e. human tumor cell lines LN229 (glioblastoma), U87 (glioblastoma), HeLa (cervix carcinoma), and H1339 (SCLC), and animal cell lines C6 (rat glioma) and GL261 (glioma). The serine protease granzyme B (GrB) derived from lysates of activated NK cells specifically binds to a sequence of Hsp70 (TKDNNLLGRFELSG, aa450-463) that mediates oligomerization of Hsp70 and is exposed on the cell surface of mHsp70 positive tumor cells. Following binding to mHsp70, GrB is specifically taken up into the cytosol and thereby induces apoptosis in a perforin-independent manner
physiological function
-
Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell proliferation in a GrB-dependent, perforin-independent manner
physiological function
-
granzyme B recoverey is closely correlated with clathriin-dependent endocytosis in NK-92 cells stimulated by target cells (primary porcine endothelial cells)
physiological function
-
GrB plays an important role in inflammatory diseases and cancer. Infiltrating immune cells during chronic inflammation results in elevated levels of GrB to diseased tissue and induces apoptosis in damaged and inflamed areas. Extracellular concentrations of GrB in bodily fluids are elevated in various diseases
physiological function
-
GrB, via extracellular matrix degradation, contributes to the establishment of the urothelial carcinoma invasive phenotype
physiological function
-
in patients with lupus erythematosus, a correlation between GrB+ lymphocyte and the presence of discoid lupus erythematosus form is found, but in dermatomyositis, GrB is poorly expressed
physiological function
-
increased T cell granzyme b production may contribute to Bronchiolitis obliterans syndrome pathogenesis and is not curtailed by current immunosuppressants
physiological function
-
it is investigated how human perforin enhances GzmB uptake in the cell: perforin activates clathrin- and Dyn-dependent endocytosis to remove perforin from the plasma membrane and enhance GzmB uptake. Both perforin and GzmB are endocytosed into giant endosomal antigen-1 endosomes that form after PFN treatment. When endocytosis is inhibited, sublytic perforin or strptolysin-O becomes lytic, causing necrosis. Consequently, inhibiting clathrin or Dyn pathways shifts the balance of target cell death by GzmB and perforin from apoptosis to necrosis
physiological function
-
TCR/CD28 mediated activation of the PI3K-mTOR pathway is important for granyzme B expression but not proliferation in regulatory T cells
physiological function
-
the effect of T-cell activation on neural progenitor cell (NPC) functions: NPC proliferation and neuronal differentiation are impaired by granzyme B released by the T-cells. GrB mediate its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltage-dependent potassium channel, Kv1.3. Blocking channel activity with margatoxin or blocking its expression reverses the inhibitory effects of GrB on neural progenitor cells
physiological function
-
granzyme B-mediated processing of IL-1alpha potently enhances the biological activity. Granzyme B does not directly influence inflammatory cytokine production by HeLa or HUVEC cells
physiological function
-
GrB is a potent IL-18 converting enzyme. GrB secreted by CTLs and/or NK cells may initiate IL-18 release from target cells, leading to the development of inflammation
physiological function
-
human neurons are selectively susceptible to granzyme B isolated from cytotoxic T cell granules. In vitro, purified human GrB induces neuronal death to the same extent as the whole activated T cell population. Following internalization through various parts of neurons, GrB accumulates in the neuronal soma. Within the cell body, GrB diffuses out of endosomes possibly through a perforin-independent mechanism and induces subsequent activation of caspases and cleavage of a-tubulin. Inhibition of caspase-3, a substrate for GrB, significantly reduces GrB-mediated neurotoxicity. Treatment of neurons with mannose-6-phosphate prevents GrB entry and inhibits GrB-mediated neuronal death
physiological function
-
proteolysis by granzyme B (GrB) enhances presentation of autoantigenic peptidylarginine deiminase 4 epitopes in rheumatoid arthritis. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles. Proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). GRAB_HUMAN
247
0
27716
Swiss-Prot
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
27400
-
x * 27400, calculated for non-activated recombinant fusion protein pro-rGBr-H6
35000
45000
35000
-
x * 35000, human, SDS-PAGE, x * 45000, human, SDS-PAGE with reducing agents
45000
-
x * 35000, human, SDS-PAGE, x * 45000, human, SDS-PAGE with reducing agents
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
enzyme interacts with either of the nuclear import receptor family members importin alpha and beta, but in addition exogenous cytosol is required for nuclear import of enzyme
?
x * 38000, recombinant inactive enzyme, SDS-PAGE, x * 37000, recombinant enterokinase-activated enzyme, SDS-PAGE
?
-
x * 27400, calculated for non-activated recombinant fusion protein pro-rGBr-H6
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
endogenous GrB is produced as a zymogen bearing an N-terminal Gly-Glu dipeptide that prevents the formation of a functional catalytic triad. Upon packaging into lytic granules inside the immune cell, GrB is processed by the dipeptidyl peptidase cathepsin C (CatC), which cleaves off GrB's Gly-Glu dipeptide and frees the newly N-terminal Ile16 residue to insert into the interior of the molecule and form a salt bridge with Asp194. The resulting conformational change enables the simultaneous generation of an oxyanion hole and maturation of the active-site S1 pocket. Endogenous GrB is activated prior to its release from the lytic granules of T cells and NK cells
proteolytic modification
proteolytic modification
-
GrB is synthesized as a zymogen (proGrB) and activated in cytotoxic granules by the lysosomal cysteine protease cathepsin C which removes the N-terminal dipeptide Gly-Glu. Cathepsin H is an additional convertase of proGrB
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
space group P2(1)2(1)2(1), cell constants a = 41.74 A, b = 114.31 A, c = 135.52, in complex with a tetrapeptide aldehyde inhibitor
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C228F
-
fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate as wild-type
C228T
-
fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate slightly lower than wild-type
C228V
-
fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate slightly lower than wild-type
Q48R/P88A/Y245H
-
common allele termed RAH, mutant enzmye has essentially identical proteolytic and cytotoxic properties to wild-type
R226G
-
replacing Arg-226 by a glycine yields an enzyme with chymase-like activity cleaving like cathepsin G after Phe
S183A
additional information
additional information
generation of a recombinant chimeric enzyme by fusion of the pre-pro-granzyme B to the epidermal growth factor receptor peptide ligand transforming growth factor alpha. Activation of the genetically modified natural killer cells by cognate target cells resulted in the release of chimeric enzyme GrB-TGFalpha together with endogenous granzymes and perforin, which augments the effector cells natural cytotoxicity against NK-sensitive tumor cells. The chimeric enzyme GrB-TGFalpha is released into the extracellular space upon induction of degranulation with phspbol-12-myristate-13-acetate and ionomycin. The secreted GrB-TGFalpha chimeric enzyme displays specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Release of GrB-TGFalpha protein from NKL/GrB-TGFalpha cells upon activation-induced degranulation
additional information
-
generation of a recombinant chimeric enzyme by fusion of the pre-pro-granzyme B to the epidermal growth factor receptor peptide ligand transforming growth factor alpha. Activation of the genetically modified natural killer cells by cognate target cells resulted in the release of chimeric enzyme GrB-TGFalpha together with endogenous granzymes and perforin, which augments the effector cells natural cytotoxicity against NK-sensitive tumor cells. The chimeric enzyme GrB-TGFalpha is released into the extracellular space upon induction of degranulation with phspbol-12-myristate-13-acetate and ionomycin. The secreted GrB-TGFalpha chimeric enzyme displays specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Release of GrB-TGFalpha protein from NKL/GrB-TGFalpha cells upon activation-induced degranulation
additional information
construction of a protein-based therapeutic platform, termed cytoplasmic oncoprotein verifier and response trigger (COVERT), which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. Fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. The rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp) highlight the COVERT platform's modularity and adaptability to diverse protease targets. Primary human T cells (Jurkat cells) can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. The COVERT platform, ENLYFQ-GrB is evaluated for its ability to selectively mediate cytotoxicity against HEK293T cells expressing TEVp. In contrast to SENP1, TEVp is not mammalian in origin, and its forced expression mimics a state of viral infection. Transient expression of GrB in HEK293T cells resulted in marked changes in cell physiology regardless of whether the cells co-expressed TEVp. Method evaluation supporting the modularity and versatility of the COVERT platform for targeting proteolytic markers of a variety of disease states, overview
additional information
-
construction of a protein-based therapeutic platform, termed cytoplasmic oncoprotein verifier and response trigger (COVERT), which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. Fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. The rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp) highlight the COVERT platform's modularity and adaptability to diverse protease targets. Primary human T cells (Jurkat cells) can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. The COVERT platform, ENLYFQ-GrB is evaluated for its ability to selectively mediate cytotoxicity against HEK293T cells expressing TEVp. In contrast to SENP1, TEVp is not mammalian in origin, and its forced expression mimics a state of viral infection. Transient expression of GrB in HEK293T cells resulted in marked changes in cell physiology regardless of whether the cells co-expressed TEVp. Method evaluation supporting the modularity and versatility of the COVERT platform for targeting proteolytic markers of a variety of disease states, overview
additional information
creation and synthesis of an antimalarial fusion protein consisting of granzyme B fused to a merozoite surface protein 4 (MSP4)-specific single-chain Fv protein (scFv), which targets the enzyme to infected erythrocytes, with up to an 8fold reduction in the IC50 of 176 nM compared to wild-type granzyme B against schizont-stage Plasmodium falciparum strain 3D7A, method, overview. Generation of a single-chain variable fragment (scFv) from an MSP4EGF-like domain-specific murine antibody, 2.44IgG1
additional information
synthesis of the GrB-superparamagnetic nanocarriers (SPIONs): preparation of superparamagnetic iron oxide nanoparticles from salt solutions FeSO4 and FeCl3 by coprecipitation, dextran is added to the nanosuspension for prevention of sedimentation. The dextran coating of the synthesized nanoparticles is cross-linked with epichlorohydrin and aminated. Activated by carbodiimide aminated-dextran is coupled to the carboxyl groups of proteins. The hydrodynamic size and electrophoretic properties of the nanoparticles are estimated. Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. GrB-functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. Magnetic targeting of the nanoparticles in vivo with a magnet placed on top of orthotopic U87 glioblastoma in NMRU nu/nu mice and C6 glioma in Wistar rats drastically enhances the accumulation of nanoparticles to the location of the magnet
additional information
-
expression of His-tagged enzyme, pro-rGrB-H6, dependent on activation by blood coagulation factor Xa, and of pro(IEPD)-rGrB-H6, engineered for self-activation, and of their C228 mutants
additional information
-
expression system for the production of high yields of enzymatic and biologically active human grB by transfection of HEK-293 with grB. The HEK-293 host cells are protected from apoptotic cell death by fusing an inactivation site coupled to a (His)6 tag to the gene sequence of GrB. Inactive grB which is actively released from HEK-293 cells by insertion of a Igkappa leader sequence is purified on a nickel column utilizing the (His)6 tag. After enterokinase digestion and heparin affinity chromatography, high yields of enzymatic and biologically active human grB are obtained
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant GST-tagged enzyme from Escherichia coli strain BL21(DE3) by ultracentrifugation, glutathione affinity chromatography and dialysis to 97% purity
recombinant His-tagged inactive enzyme from HEK-293 cells by nickel affinity chromatography, enzyme activation by enterokinase, and further purification by heparin affinity chromatography
recombinant His6-tagged inactive enzyme from HEK 293 EBNA cells by nickel affinity chromatography, activation by enterokinase proteolytic cleavage
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
ectopic expression of granzyme B-epidermal growth factor receptor peptide ligand transforming growth factor alpha chimeric enzyme GrB-TGFalpha in natural killer cells from a lentiviral vector, the fusion enzyme shows enhanced natural cytotoxicity and increased specific killing of tumor cells
functional recombinant expression of GST-tagged enzyme in Escherichia coli strain BL21(DE3)
sequence comparisons and phylogenetic analysis, recombinant expression of inactive enzyme with N-terminal His6-tag followed by an enterokinase (EK) site in HEK 293 EBNA cells
active GzmH and mutant S182A with a C-terminal 6 x His-tag coding sequence subcloned into vector pPICZalpha and expressed in Pichia pastoris. Jurkat or HeLa cells loaded with GzmH
-
expressed in bacteria and eukaryotic cells. The large scale production of recombinant GzmB in bacteria may necessitate refolding, but this is easily achieved in optimized detergent-free refolding buffers
-
leukocyte cDNA amplified by PCR, expressed in a baculovirus system in Sf9 cells
-
recombinant granzyme B expressed in Pichia pastoris as a chimeric zymogen comprising the alpha-factor signal sequence, a prodomain including an enterokinase cleavage site, and the mature granzyme B sequence followed by a hexahistidine tag, cloned and expressed in Escherichia coli, resulting fusion protein is insoluble and folded incorrectly
-
recombinant, nonglycosylated GzmH and GzmH mutant expressed in Escherichia coli
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
enzyme expression is decreased in natural killer cells following immunosuppressive therapy
extracellular levels of the enzyme are elevated in the bodily fluids in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis
increased circulating granzyme B in type 2 diabetes patients with low-grade systemic inflammation
serine protease inhibitor A3N, i.e. serpin A3N or SA3N, an extracellular inhibitor of GrB possessing multiple biological functions, including the attenuaxadtion of muscular dystrophy in mice, neuropathic pain, and GrB-mediated decorin cleavage and rupture. It also induces neuroprotection in vitro and in vivo. Role of GrB inhibitor SA3N on Escherichia coli LPS-induced inflammation in NK-92 cells. SA3N pretreatment prevents the LPS-induced changes in expression levels of GRP78, CHOP, NF-kappaB and IkappaBalpha proteins. Also SA3N pretreatment prevents the expression and exocytosis of GrB by LPS
expression of granzyme B is higher in patients with Bronchiolitis obliterans syndrome than in patients with acute lung transplant rejection
-
expression of GrB mRNA is upregulated in active lesions of multiple sclerosis patients and in activated T cells
-
GrB expression in plasmacytoid dendritic cells is strictly regulated on a transcriptional level involving Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and STAT5. Interleukin-3 (IL-3), secreted by activated T cells, plays a central role for GrB induction
-
GrB in urothelial cancer tissues is concentrated at the cancer invasion front and is expressed in neoplastic cells undergoing epithelial-mesenchymal transition, a key event in carcinoma invasion
-
in blood, bronchoalveolar lavage (BAL) and large airway brushing expression of granzyme B is significantly increased in lung transplant patients
-
regulatory T cells (Tregs) freshly isolated from the peripheral blood of normal adults lack granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, express high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone fail to induce granzyme B
-
serum levels of GrB are elevated in several diseases such as human immunodeficiency virus-1 infection, Epstein-Barr virus infection, arthritis and others
-
treatment of regulatory T cells (Tregs) with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppresses granzyme B expression
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
increased detection of the enzyme in cytotoxic T lymphocytes and natural killer cells are an immune signature for lymphocyte activation in hemophagocytic lymphohistiocytosis, irrespective of genetic subtype, and may also be a useful measure of immune activation in other related conditions
pharmacology
analysis
-
caution in the design and interpretation of experiments using GrBs from different species due to distinct tetrapeptide specificities and abilities to recruit the BID pathway
biotechnology
-
engineering of mutant enzyme suitable for cleavage of fusion proteins
degradation
-
human and murine GzmB are distinct enzymes with different substrate preferences. Subtle differences in enzyme structure can radically affect substrate selection. Caspases are not essential for apoptosis initiated by human GzmB
medicine
synthesis
-
expression system for the production of high yields of enzymatic and biologically active human grB by transfection of HEK-293 with grB. The HEK-293 host cells are protected from apoptotic cell death by fusing an inactivation site coupled to a (His)6 tag to the gene sequence of GrB. Inactive grB which is actively released from HEK-293 cells by insertion of a Igkappa leader sequence is purified on a nickel column utilizing the (His)6 tag. After enterokinase digestion and heparin affinity chromatography, high yields of enzymatic and biologically active human grB are obtained
additional information
pharmacology
granzyme B has antimalarial activity against Plasmodium falciparum strain 3D7A of 1600 nM and can be targeted delivered by a granzyme B-single-chain Fv fusion protein, inhibitory activities on parasite growth of different fusion proteins on two different Plasmodium falciparum strains, overview
pharmacology
antimalarial activity of granzyme B and its targeted delivery by a granzyme B-single-chain Fv fusion protein. Therapeutic efficacies of recombinant antibody-mediated antimalarial immunotherapeutics based on granzyme B, overview
pharmacology
functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. GrB-functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. GrB-SPIONs accumulate in the tumor and increase MR contrast enhancement. The therapeutic potential of a systemic administration of GrB-SPIONs is evaluated in o.t. xenograft H1339 lung cancer model with and without brain metastases and U87 glioma mouse models, overview
medicine
-
A streptolysin-O/GrB combination results in the induction of p53 accumulation and transcriptional activity associated with strong induction of apoptotic cell death in T1 cells
medicine
-
can induce rapid apoptosis of target cells, which is dependent on caspase activation and mitochondrial damage. GzmH-induced death is characterized by phosphatidylserine externalization, nuclear condensation, DNA fragmentation, caspase activation and cytochrome c release. GzmH may play an essential role in caspase-dependent pathogen clearance in the innate immunity that may complement the proapoptotic function of GzmB in human natural killer cells
medicine
-
detection of target GzB activity followed by caspase 3 activation provides a unique readout of a potentially lethal injury delivered by cytotoxic lymphocytes
medicine
-
ELISPOT measurements of granzyme B permit the identification of actively ongoing CD8+ cell responses. Importance for immune diagnostic of infections, transplantation, allergies, autoimmune diseases, tumors and vaccine development
medicine
-
expression of granzyme B by peripheral CD8+ T lymphocytes does not vary between emphysematous smokers, smokers and non-smokers with normal lung function
medicine
-
extension of the present standard of IFN-gamma measurements to the analysis of GzB and perforin release in functional T cell assays will provide new insights into CD8+ effector T cell function in HIV infection
medicine
-
granzyme B may play a key role in ateromatous diseases. Role in cardiac allograft vasculopathy and atherosclerosis
medicine
-
granzyme B plays a role in the cytotoxic response in lichen planus. It is a probable target for future immunomodulator therapy
medicine
-
granzyme H participates in the anti-adenovirus response by both inhibiting virus replication directly and simultaneously re-sensitizing infected cell to granzyme B-induced cell death
medicine
-
granzymes can mediate antiviral activity through direct cleavage of viral substrates. Different granzymes have synergistic functions to outflank viral defenses that block host antiviral activities
medicine
-
GrB proteolysis of Hsc70/Hsp70-interacting protein is important to the efficiency of death induction
medicine
-
GzmH induces cell death, it is nearly as potent as GzmB. Exhibits an alternative cell death pathway in innate immunity. In contrast to GzmB, GzmH achieves cell death by acting on mitochondrial and nuclear targets but not through the activation of hallmark apoptotic substrates
medicine
-
key role of plasticity in the granzyme B mediated cell death pathway in the killing of changed tumor cells, resulting in keratoacanthoma regression through apoptosis or direct damage of tumor cells. Insufficient activation of cytotoxic T lymphocytes and decreased release or activity of granzyme B may be responsible for squamous cell-carcinoma progression and occasional aggressive behavior in keratoacanthomas. Targeted delivery of granzyme B to squamous cell, carcinoma cells may be a new agent that may have an additive or synergic effect with conventional therapeutic modalities, since there are still no known cellular resistance mechanisms capable of protecting cells against all granzyme B mediated pathways
medicine
-
extracellular granzyme B may help control localized coagulation during inflammation
medicine
-
granzyme B level may contribute to a diagnosis of immune-mediated epilepsy including Rasmussen syndrome
medicine
-
granzyme B may be the limiting factor in adaptive regulatory T cell-mediated K562 target cell killing
medicine
-
plasma granzyme B level on day 14 is a significant predicting factor for left ventricular remodeling after acute myocardial infarction
medicine
-
potential role for granzyme B in the process of initiation of myasthenia gravis
medicine
-
the release of granzyme B through two routes from unconjugated cytotoxic lymphocytes suggests that it functions outside the cell and may contribute to pathology in cases of immune dysregulation, such as familial hemophagocytic lymphohistiocytosis
medicine
-
granzyme B GrB labels a subpopulation of effector cells involved in ongoing cytotoxic action should be considered as a specific marker showing the extent of the direct local cytotoxic damage in patients with lupus erythematosus
medicine
-
modified versions of GzmB with lower isoelectric points can be utilized without loss of apoptosis-inducing potential but fewer side activities
medicine
-
since GzmB is very effective in killing human tumor cell lines that are resistant against cytotoxic drugs GrzmB is used as an effector domain in potential immunoconjugates
medicine
-
both GzmA and GzmB levels are significantly increased in serum of patients with patients with amyotrophic lateral sclerosis. There is a significant correlation of serum GzmB levels with severity of clinical state of amyotrophic lateral sclerosis patients
medicine
-
human neurons are selectively susceptible to granzyme B isolated from cytotoxic T cell granules. In vitro, purified human GrB induces neuronal death to the same extent as the whole activated T cell population. Following internalization through various parts of neurons, GrB accumulates in the neuronal soma. Within the cell body, GrB diffuses out of endosomes possibly through a perforin-independent mechanism and induces subsequent activation of caspases and cleavage of a-tubulin. Inhibition of caspase-3, a substrate for GrB, significantly reduces GrB-mediated neurotoxicity. Treatment of neurons with mannose-6-phosphate prevents GrB entry and inhibits GrB-mediated neuronal death
medicine
-
internalization of grB by membrane Hsp70 positive tumor cells is dependent on mammalian glycosylation of GrB. Neuraminic acid blocks binding of GrB to CT26 tumor cells
medicine
-
ischemic brain samples after stroke contain significantly higher levels of Gra-b and interferon-gamma inducible protein-10 than non-ischemic controls. In stroke, poly(ADP-ribose) polymerase-1 and heat shock protein-70 are cleaved to canonical proteolytic signature fragments by Gra-b. Gra-b also binds to Bid and caspase-3 and colocalizesw with Annexin-V+/TUNEL+ in degenerating neurons. Gra-b inhibition protects both normal and ischemia-reperfused neurons against in vitro neurotoxicity mediated by activated CG-SH cells and supernatants. Increased leukocyte infiltration and elevated Gra-b levels in the post-stroke brain can induce contact-dependent and independent post-ischemic neuronal death to aggravate stroke injury
medicine
-
the precursor frequency and cytotoxic lymphocyte activity of HLA-A2-restricted transaldolase 168-176-specific CD8+ T cells is increased in multiple sclerosis patients. The major C-terminal GrB cleavage product of transaldolase, residues 28-337, has no enzymatic activity but retains the antigenicity of full-length transaldolase, effectively stimulating the proliferation and cytotoxic lymphocyte activity of peripheral blood mononuclear cells and of CD8+ T cell lines from patients with multiple sclerosis. Sera of multiple sclerosis patients exhibit similar binding affinity to wild-type and GrB-cleaved transaldolase
medicine
-
The soluble granzyme B levels are higher in systemic lupus erythematosus patients and associated with various clinical features like reduced complement components, C3 and C4, and skin lesion. The soluble granzyme B levels are also sturdily related with severity of the disease. Excessive secretion of soluble granzyme B and enhanced activity of cytotoxic T lymphocyte may play a vital role in the pathogenesis of systemic lupus erythematosus and organ damage
additional information
-
role for granzyme B in the dismantling of the cytoskeleton. In the execution phase of apoptosis it may modify key structural proteins thus enabling the cell to be properly dismantled and eliminated by phagocytosis
additional information
-
ability of gzmH to cleave host proteins involved in essential viral functions provides a novel mechanism by which granzymes can mediate direct antiviral activities
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Homo sapiens, Mus musculus
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Homo sapiens
Estebanez-Perpina, E.; Fuentes-Prior, P.; Belorgey, D.; Braun, M.; Kiefersauer, R.; Maskos, K.; Huber, R.; Rubin, H.; Bode, W.
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Homo sapiens
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Immunity
8
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1998
Homo sapiens
Kanamori, H.; Krieg, S.; Mao, C.; Di Pippo, V.A.; Wang, S.; Zajchowski, D.A.; Shapiro, D.J.
Proteinase inhibitor 9, an inhibitor of granzyme B-mediated apoptosis, is a primary estrogen-inducible gene in human liver cells
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2000
Homo sapiens
Sun, J.; Whisstock, J.C.; Harriott, P.; Walker, B.; Novak, A.; Thompson, P.E.; Smith, A.I.; Bird, P.I.
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Homo sapiens
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Purification and use of granzyme B
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2000
Homo sapiens, Mus musculus, Rattus norvegicus
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A novel domain in adenovirus L4-100K is required for stable binding and efficient inhibition of human granzyme B: possible interaction with a species-specific exosite
Mol. Cell. Biol.
23
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2003
Homo sapiens, Mus musculus, Rattus norvegicus
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Cell binding, internalization and cytotoxic activity of human granzyme B expressed in the yeast Pichia pastoris
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394
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2006
Homo sapiens
Grossman, W.J.; Verbsky, J.W.; Tollefsen, B.L.; Kemper, C.; Atkinson, J.P.; Ley, T.J.
Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells
Blood
104
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2004
Homo sapiens
Mahrus, S.; Craik, C.S.
Selective chemical functional probes of granzymes A and B reveal granzyme B Is a major effector of natural killer cell-mediated lysis of target cells
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2005
Homo sapiens
Sun, J.; Bird, C.H.; Thia, K.Y.; Matthews, A.Y.; Trapani, J.A.; Bird, P.I.
Granzyme B encoded by the commonly occurring human RAH allele retains pro-apoptotic activity
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279
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2004
Homo sapiens
Loeb, C.R.; Harris, J.L.; Craik, C.S.
Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance towards apoptosis
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281
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2006
Homo sapiens
Blink, E.J.; Jiansheng, Z.; Hu, W.; Calanni, S.T.; Trapani, J.A.; Bird, P.I.; Jans, D.A.
Interaction of the nuclear localizing cytolytic granule serine protease granzyme B with importin alpha or beta: modulation by the serpin inhibitor PI-9
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2005
Homo sapiens
Lorentsen, R.H.; Fynbo, C.H.; Thogersen, H.C.; Etzerodt, M.; Holtet, T.L.
Expression, refolding, and purification of recombinant human granzyme B
Protein Expr. Purif.
39
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2005
Homo sapiens
Kuerten, S.; Nowacki, T.M.; Kleen, T.O.; Asaad, R.J.; Lehmann, P.V.; Tary-Lehmann, M.
Dissociated production of perforin, granzyme B, and IFN-gamma by HIV-specific CD8(+) cells in HIV infection
AIDS Res. Hum. Retroviruses
24
62-71
2008
Homo sapiens
Fellows, E.; Gil-Parrado, S.; Jenne, D.E.; Kurschus, F.C.
Natural killer cell-derived human granzyme H induces an alternative, caspase-independent cell-death program
Blood
110
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2007
Homo sapiens
Chamberlain, C.M.; Granville, D.J.
The role of Granzyme B in atheromatous diseases
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85
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2007
Homo sapiens, Mus musculus
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Granzyme B production distinguishes recently activated CD8(+) memory cells from resting memory cells
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2007
Homo sapiens
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Homo sapiens
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Homo sapiens
Casciola-Rosen, L.; Garcia-Calvo, M.; Bull, H.G.; Becker, J.W.; Hines, T.; Thornberry, N.A.; Rosen, A.
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Homo sapiens
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Homo sapiens
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Possible key role of granzyme B in keratoacanthoma regression
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Homo sapiens
Strik, M.C.; de Koning, P.J.; Kleijmeer, M.J.; Bladergroen, B.A.; Wolbink, A.M.; Griffith, J.M.; Wouters, D.; Fukuoka, Y.; Schwartz, L.B.; Hack, C.E.; van Ham, S.M.; Kummer, J.A.
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Homo sapiens
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45
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Homo sapiens
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H is for helper: granzyme H helps granzyme B kill adenovirus-infected cells
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Homo sapiens, Mus musculus
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Homo sapiens, Equus caballus (Q2A6L4), Equus caballus
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Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity
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179
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2009
Homo sapiens, Mus musculus
Besenicar, M.P.; Metkar, S.; Wang, B.; Froelich, C.J.; Anderluh, G.
Granzyme B translocates across the lipid membrane only in the presence of lytic agents
Biochem. Biophys. Res. Commun.
371
391-394
2008
Homo sapiens
Romero, V.; Fellows, E.; Jenne, D.E.; Andrade, F.
Cleavage of La protein by granzyme H induces cytoplasmic translocation and interferes with La-mediated HCV-IRES translational activity
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16
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2009
Homo sapiens
Nishimura, M.; Sato, H.; Okazaki, H.; Satake, M.; Tadokoro, K.
Interleukin-10 containing normal human serum inhibits granzyme B release but not perforin release from alloreactive and EBV-specific T cell clones
Cell. Immunol.
251
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2008
Homo sapiens
Kondo, H.; Hojo, Y.; Tsuru, R.; Nishimura, Y.; Shimizu, H.; Takahashi, N.; Hirose, M.; Ikemoto, T.; Ohya, K.; Katsuki, T.; Yashiro, T.; Shimada, K.
Elevation of plasma granzyme B levels after acute myocardial infarction
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Homo sapiens
Takahashi, Y.; Mine, J.; Kubota, Y.; Yamazaki, E.; Fujiwara, T.
A substantial number of Rasmussen syndrome patients have increased IgG, CD4(+) T cells, TNFalpha, and granzyme B in CSF
Epilepsia
50
1419-1431
2009
Homo sapiens
Prakash, M.D.; Bird, C.H.; Bird, P.I.
Active and zymogen forms of granzyme B are constitutively released from cytotoxic lymphocytes in the absence of target cell engagement
Immunol. Cell Biol.
87
249-254
2009
Homo sapiens
Bratke, K.; Goettsching, H.; Kuepper, M.; Geyer, S.; Luttmann, W.; Virchow, J.C.
Interleukin-4 suppresses the cytotoxic potential of in vitro generated, adaptive regulatory CD4(+) T cells by down-regulation of granzyme B
Immunology
127
338-344
2008
Homo sapiens
Buzza, M.S.; Dyson, J.M.; Choi, H.; Gardiner, E.E.; Andrews, R.K.; Kaiserman, D.; Mitchell, C.A.; Berndt, M.C.; Dong, J.F.; Bird, P.I.
Antihemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor
J. Biol. Chem.
283
22498-22504
2008
Homo sapiens
Araki, Y.; Fann, M.; Wersto, R.; Weng, N.P.
Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B)
J. Immunol.
180
8102-8108
2008
Homo sapiens
Chattopadhyay, P.K.; Betts, M.R.; Price, D.A.; Gostick, E.; Horton, H.; Roederer, M.; De Rosa, S.C.
The cytolytic enzymes granyzme A, granzyme B, and perforin: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression
J. Leukoc. Biol.
85
88-97
2009
Homo sapiens
Casciola-Rosen, L.; Miagkov, A.; Nagaraju, K.; Askin, F.; Jacobson, L.; Rosen, A.; Drachman, D.B.
Granzyme B: evidence for a role in the origin of myasthenia gravis
J. Neuroimmunol.
201-202
33-40
2008
Homo sapiens
Van Damme, P.; Maurer-Stroh, S.; Plasman, K.; Van Durme, J.; Colaert, N.; Timmerman, E.; De Bock, P.J.; Goethals, M.; Rousseau, F.; Schymkowitz, J.; Vandekerckhove, J.; Gevaert, K.
Analysis of protein processing by N-terminal proteomics reveals novel species-specific substrate determinants of granzyme B orthologs
Mol. Cell. Proteomics
8
258-272
2009
Homo sapiens, Mus musculus
Jahrsdoerfer, B.; Vollmer, A.; Blackwell, S.E.; Maier, J.; Sontheimer, K.; Beyer, T.; Mandel, B.; Lunov, O.; Tron, K.; Nienhaus, G.U.; Simmet, T.; Debatin, K.M.; Weiner, G.J.; Fabricius, D.
Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion
Blood
115
1156-1165
2010
Homo sapiens
Thiery, J.; Keefe, D.; Saffarian, S.; Martinvalet, D.; Walch, M.; Boucrot, E.; Kirchhausen, T.; Lieberman, J.
Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis
Blood
115
1582-1593
2010
Homo sapiens
Efimova, O.V.; Kelley, T.W.
Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway
BMC Immunol.
10
59
2009
Homo sapiens
Darrah, E.; Rosen, A.
Granzyme B cleavage of autoantigens in autoimmunity
Cell Death Differ.
17
624-632
2010
Homo sapiens
Xie, D.; Hai, B.; Xie, X.; Liu, L.; Ayello, J.; Ma, X.; Zhang, J.
Peripheral CD4+CD8+cells are the activated T cells expressed granzyme B (GrB), Foxp3, interleukin 17 (IL-17), at higher levels in Th1/Th2 cytokines
Cell. Immunol.
259
157-164
2009
Homo sapiens
Li, P.; Zheng, G.; Yang, Y.; Zhang, C.; Xiong, P.; Xu, Y.; Fang, M.; Tan, Z.; Zheng, F.; Gong, F.
Granzyme B is recovered by natural killer cells via clathrin-dependent endocytosis
Cell. Mol. Life Sci.
67
3197-3208
2010
Homo sapiens
Grassi, M.; Capello, F.; Bertolino, L.; Seia, Z.; Pippione, M.
Identification of granzyme B-expressing CD-8-positive T cells in lymphocytic inflammatory infiltrate in cutaneous lupus erythematosus and in dermatomyositis
Clin. Exp. Dermatol.
34
910-914
2009
Homo sapiens
Hodge, S.; Hodge, G.; Ahern, J.; Liew, C.L.; Hopkins, P.; Chambers, D.C.; Reynolds, P.N.; Holmes, M.
Increased levels of T cell granzyme b in bronchiolitis obliterans syndrome are not suppressed adequately by current immunosuppressive regimens
Clin. Exp. Immunol.
158
230-236
2009
Homo sapiens
Hagn, M.; Ebel, V.; Sontheimer, K.; Schwesinger, E.; Lunov, O.; Beyer, T.; Fabricius, D.; Barth, T.F.; Viardot, A.; Stilgenbauer, S.; Hepp, J.; Scharffetter-Kochanek, K.; Simmet, T.; Jahrsdoerfer, B.
CD5(+) B cells from individuals with systemic lupus erythematosus express granzyme B
Eur. J. Immunol.
40
2060-2069
2010
Homo sapiens
Kurschus, F.; Jenne, D.
Delivery and therapeutic potential of human granzyme B
Immunol. Rev.
235
159-171
2010
Homo sapiens, Mus musculus
D'Eliseo, D.; Pisu, P.; Romano, C.; Tubaro, A.; De Nunzio, C.; Morrone, S.; Santoni, A.; Stoppacciaro, A.; Velotti, F.
Granzyme B is expressed in urothelial carcinoma and promotes cancer cell invasion
Int. J. Cancer
127
1283-1294
2009
Homo sapiens
D'Angelo, M.E.; Bird, P.I.; Peters, C.; Reinheckel, T.; Trapani, J.A.; Sutton, V.R.
Cathepsin H is an additional convertase of pro-granzyme B
J. Biol. Chem.
285
20514-20519
2010
Homo sapiens, Mus musculus
Wang, T.; Lee, M.H.; Johnson, T.; Allie, R.; Hu, L.; Calabresi, P.A.; Nath, A.
Activated T-cells inhibit neurogenesis by releasing granzyme B: rescue by Kv1.3 blockers
J. Neurosci.
30
5020-5027
2010
Homo sapiens
Boivin, W.A.; Cooper, D.M.; Hiebert, P.R.; Granville, D.J.
Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma
Lab. Invest.
89
1195-1220
2009
Homo sapiens, Mus musculus
van Tetering, G.; Bovenschen, N.; Meeldijk, J.; van Diest, P.J.; Vooijs, M.
Cleavage of Notch1 by granzyme B disables its transcriptional activity
Biochem. J.
437
313-322
2011
Homo sapiens
Chaitanya, G.V.; Eeka, P.; Munker, R.; Alexander, J.S.; Babu, P.P.
Role of cytotoxic protease granzyme-b in neuronal degeneration during human stroke
Brain Pathol.
21
16-30
2011
Homo sapiens
Shah, D.; Kiran, R.; Wanchu, A.; Bhatnagar, A.
Soluble granzyme B and cytotoxic T lymphocyte activity in the pathogenesis of systemic lupus erythematosus
Cell. Immunol.
269
16-21
2011
Homo sapiens
Ilzecka, J.
Granzymes A and B levels in serum of patients with amyotrophic lateral sclerosis
Clin. Biochem.
44
650-653
2011
Homo sapiens
Afonina, I.; Cullen, S.; Martin, S.
Cytotoxic and non-cytotoxic roles of the CTL/NK protease granzyme B
Immunol. Rev.
235
105-116
2010
Homo sapiens
Omoto, Y.; Yamanaka, K.; Tokime, K.; Kitano, S.; Kakeda, M.; Akeda, T.; Kurokawa, I.; Gabazza, E.C.; Tsutsui, H.; Katayama, N.; Yamanishi, K.; Nakanishi, K.; Mizutani, H.
Granzyme B is a novel interleukin-18 converting enzyme
J. Dermatol. Sci.
59
129-135
2010
Homo sapiens
Gehrmann, M.; Doss, B.T.; Wagner, M.; Zettlitz, K.A.; Kontermann, R.E.; Foulds, G.; Pockley, A.G.; Multhoff, G.
A novel expression and purification system for the production of enzymatic and biologically active human granzyme B
J. Immunol. Methods
371
8-17
2011
Homo sapiens
Niland, B.; Miklossy, G.; Banki, K.; Biddison, W.E.; Casciola-Rosen, L.; Rosen, A.; Martinvalet, D.; Lieberman, J.; Perl, A.
Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients
J. Immunol.
184
4025-4032
2010
Homo sapiens
Haile, Y.; Simmen, K.C.; Pasichnyk, D.; Touret, N.; Simmen, T.; Lu, J.Q.; Bleackley, R.C.; Giuliani, F.
Granule-derived granzyme B mediates the vulnerability of human neurons to T cell-induced neurotoxicity
J. Immunol.
187
4861-4872
2011
Homo sapiens
Kapelski, S.; de Almeida, M.; Fischer, R.; Barth, S.; Fendel, R.
Antimalarial activity of granzyme B and its targeted delivery by a granzyme B-single-chain Fv fusion protein
Antimicrob. Agents Chemother.
59
669-672
2015
Homo sapiens (P10144)
Mellor-Heineke, S.; Villanueva, J.; Jordan, M.B.; Marsh, R.; Zhang, K.; Bleesing, J.J.; Filipovich, A.H.; Risma, K.A.
Elevated granzyme B in cytotoxic lymphocytes is a signature of immune activation in hemophagocytic lymphohistiocytosis
Front. Immunol.
4
72
2013
Homo sapiens (P10144), Homo sapiens
Bhela, S.; Kempsell, C.; Manohar, M.; Dominguez-Villar, M.; Griffin, R.; Bhatt, P.; Kivisakk-Webb, P.; Fuhlbrigge, R.; Kupper, T.; Weiner, H.; Baecher-Allan, C.
Nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell (Treg) suppression by HLA-DR-CD25hiCD127lo tregs in multiple sclerosis and in response to IL-6
J. Immunol.
194
2180-2189
2015
Homo sapiens (P10144), Homo sapiens
Kim, M.S.; Buisson, L.A.; Heathcote, D.A.; Hu, H.; Braddock, D.C.; Barrett, A.G.; Ashton-Rickardt, P.G.; Snyder, J.P.
Approaches to design non-covalent inhibitors for human granzyme B (hGrB)
Org. Biomol. Chem.
12
8952-8965
2014
Homo sapiens (P10144), Homo sapiens
Boivin, W.A.; Shackleford, M.; Vanden Hoek, A.; Zhao, H.; Hackett, T.L.; Knight, D.A.; Granville, D.J.
Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-beta1
PLoS ONE
7
e33163
2012
Homo sapiens (P10144)
Oberoi, P.; Jabulowsky, R.A.; Baehr-Mahmud, H.; Wels, W.S.
EGFR-targeted granzyme B expressed in NK cells enhances natural cytotoxicity and mediates specific killing of tumor cells
PLoS ONE
8
e61267
2013
Homo sapiens (P10144), Homo sapiens
Li, X.; Zhang, G.; An, G.; Liu, S.; Lai, Y.
Expression, purification and anticancer analysis of GST-tagged human perforin and granzyme B proteins in human laryngeal cancer Hep-2 cells
Protein Expr. Purif.
95
38-43
2014
Homo sapiens (P10144), Homo sapiens
Ho, P.; Ede, C.; Chen, Y.Y.
Modularly constructed synthetic granzyme B molecule enables interrogation of intracellular proteases for targeted cytotoxicity
ACS Synth. Biol.
6
1484-1495
2017
Homo sapiens (P10144), Homo sapiens
Kapelski, S.; De Almeida, M.; Fischer, R.; Barth, S.; Fendel, R.
Antimalarial activity of granzyme B and its targeted delivery by a granzyme B-single-chain Fv fusion protein
Antimicrob. Agents Chemother.
59
669-672
2015
Homo sapiens (P10144)
Dotiwala, F.; Sen Santara, S.; Binker-Cosen, A.A.; Li, B.; Chandrasekaran, S.; Lieberman, J.
Granzyme B disrupts central metabolism and protein synthesis in bacteria to promote an immune cell death program
Cell
171
1125-1137
2017
Homo sapiens (P10144), Homo sapiens
Kumar, A.; Perdomo, M.F.; Kantele, A.; Hedman, L.; Hedman, K.; Franssila, R.
Granzyme B mediated function of parvovirus B19-specific CD4+ T cells
Clin. Transl. Immunology
4
e39
2015
Homo sapiens (P10144)
Cimini, F.A.; DEliseo, D.; Barchetta, I.; Bertoccini, L.; Velotti, F.; Cavallo, M.G.
Increased circulating granzyme B in type 2 diabetes patients with low-grade systemic inflammation
Cytokine
115
104-108
2019
Homo sapiens (P10144), Homo sapiens
Darrah, E.; Kim, A.; Zhang, X.; Boronina, T.; Cole, R.N.; Fava, A.; Giles, J.T.; Bingham III, C.O.; Chalmers, M.J.; Griffin, P.R.; Sadegh-Nasseri, S.; Rosen, A.
Proteolysis by granzyme B enhances presentation of autoantigenic peptidylarginine deiminase 4 epitopes in rheumatoid arthritis
J. Proteome Res.
16
355-365
2017
Homo sapiens
Wang, L.; Jiang, S.; Xiao, L.; Chen, L.; Zhang, Y.; Tong, J.
Inhibition of granzyme B activity blocks inflammation induced by lipopolysaccharide through regulation of endoplasmic reticulum stress signaling in NK92 cells
Mol. Med. Rep.
18
580-586
2018
Homo sapiens (P10144)
Fu, Z.; Thorpe, M.; Akula, S.; Hellman, L.
Asp-ase activity of the Opossum granzyme B supports the role of granzyme B as part of anti-viral immunity already during early mammalian evolution
PLoS ONE
11
e0154886
2016
Monodelphis domestica, Homo sapiens (P10144), Homo sapiens
Marcet-Palacios, M.; Ewen, C.; Pittman, E.; Duggan, B.; Carmine-Simmen, K.; Fahlman, R.; Bleackley, R.
Design and characterization of a novel human granzyme B inhibitor
Protein Eng. Des. Sel.
28
9-17
2015
Homo sapiens (P10144), Homo sapiens
Shevtsov, M.; Stangl, S.; Nikolaev, B.; Yakovleva, L.; Marchenko, Y.; Tagaeva, R.; Sievert, W.; Pitkin, E.; Mazur, A.; Tolstoy, P.; Galibin, O.; Ryzhov, V.; Steiger, K.; Smirnov, O.; Khachatryan, W.; Chester, K.; Multhoff, G.
Granzyme B functionalized nanoparticles targeting membrane Hsp70-positive tumors for multimodal cancer theranostics
Small
15
e1900205
2019
Homo sapiens (P10144)
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