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Information on EC 3.4.22.64 - caspase-11
for references in articles please use BRENDA:EC3.4.22.64
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.22 Cysteine endopeptidases
3.4.22.64 caspase-11
IUBMB Comments
This murine enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36), caspase-4 (EC 3.4.22.57) and caspase-5 (EC 3.4.22.58) in humans and caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation. Like caspase-5, but unlike caspase-4, this enzyme can be induced by lipopolysaccharide . This enzyme not only activates caspase-1, which is required for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, but it also activates caspase-3 (EC 3.4.22.56), which leads to cellular apoptosis under pathological conditions [1,2]. Belongs in peptidase family C14.
The enzyme appears in viruses and cellular organisms
- 3.4.22.64
- inflammasome
-
pyroptosis
- lps
- lipopolysaccharide
-
non-canonical
-
gasdermin
- sepsis
-
gsdmd
- interleukin-1
-
lps-induced
- pyrin
-
casp11
-
apoptosis-associated
-
nod-like
- caspase-5
-
pore-forming
-
speck-like
-
guanylate-binding
-
inflammasome-mediated
- wedelolactone
- rodentium
-
pyroptosis-related
-
inflammasome-dependent
-
caspase-1/11
-
caspase-1-mediated
-
bmdms
-
speck
- thailandensis
- medicine
Reaction Schemes
showstrict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-/-
Synonyms
caspase-11, casp4, caspase 11, ich-3, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
C14.012
-
-
-
-
CASP11
CASP4
caspase-11
caspase-4
ICH-3 protease
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-/-
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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CAS REGISTRY NUMBER
COMMENTARY
216503-96-7
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-VEHD-7-amido-4-methylcoumarin + H2O
acetyl-VEHD + 7-amino-4-methylcoumarin
-
Substrates: -
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?
acetyl-WEHD-7-amido-4-methylcoumarin + H2O
acetyl-WEHD + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
DABYL-GQLSLLSDGID-Glu + H2O
?
Substrates: synthetic substrate
Products: -
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?
gasdermin D + H2O
gasdermin fragment p30 + gasdermin fragment p20
-
Substrates: -
Products: -
Products: -
?
gasdermin D + H2O
N-terminal domain of gasdermin D + C-terminal domain of gasdermin D
Substrates: -
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: i.e. TRPC1, plays a role in regulating innate immunity by modulating channel complexes during inflammatory responses
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: i.e. TRPC1, plays a role in regulating innate immunity by modulating channel complexes during inflammatory responses
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
gasdermin D + H2O
?
Substrates: cleavage of gasdermin D (GSDMD) into pore-forming peptides
Products: -
Products: -
?
gasdermin D + H2O
?
Substrates: -
Products: -
Products: -
?
procaspase-1 + H2O
?
-
Substrates: the enzyme is an upstream activator of caspase-1
Products: -
Products: -
?
procaspase-3 + H2O
?
-
Substrates: the enzyme is a critical initiator caspase responsible for the activation of caspase-3
Products: -
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?
additional information
?
-
-
Substrates: optimal cleavage site is IEHD, LEHD, VEHD or PEHD
Products: -
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?
additional information
?
-
-
Substrates: overexpression induces apoptosis
Products: -
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?
additional information
?
-
-
Substrates: phenotype of animals deficient in caspase-11: resistant to lipopolysaccharide-induced caspase-1 processing, interleukin-1alpha and interleukin-beta secretion, and endotoxic shock
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is a critical initiator caspase responsible for the activation of caspase-3. The enzyme is an upstream activator of caspase-1. Caspase-11 deficient animals have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion. The enzyme is A VERY IMPORTANT REGULATOR OF APOPTOSIS
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Products: -
?
additional information
?
-
-
Substrates: enzyme is involved in cytokine activation
Products: -
Products: -
?
additional information
?
-
-
Substrates: pro-caspase-11 physically interacts with pro-ICE in cells, the expression of casp-11 is essential for activation of ICE. Caspase-11 is a compinent of ICE complex and is required for the activation of ICE. Important role of ICE and caspase-11 in mediating apoptosis in pathological conditions
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?
additional information
?
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in cytokine activation
Products: -
Products: -
?
additional information
?
-
-
Substrates: neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice
Products: -
Products: -
?
additional information
?
-
-
Substrates: C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation
Products: -
Products: -
?
additional information
?
-
-
Substrates: neurotoxicity of 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade
Products: -
Products: -
?
additional information
?
-
-
Substrates: caspase-11 has a regulatory role in ethanol-induced apoptosis. Suppression of caspase-11 expression may be a mechanism by which Scutellariae radix (Chinese herbal medicine) exerts its cytoprotective effect
Products: -
Products: -
?
additional information
?
-
-
Substrates: caspase-11 may be a central regulator of multiple events, including cell migration, cytokine maturation and apoptosis, during inflammation responses. Caspase-11 interacts physically and functionally with actin interacting protein 1, an activator of cofilin-mediated actin depolymerization. Caspase-11 and actin interacting protein 1 work cooperatively to promote cofilin-mediated actin depolymerization
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Products: -
?
additional information
?
-
-
Substrates: a pathway modulating inflammatory-cell migration involve caspase-11 and actin interacting protein 1
Products: -
Products: -
?
additional information
?
-
-
Substrates: Flightless-I regulates the subcellular distribution of caspase-11 by promoting its localization at the cell leading edge
Products: -
Products: -
?
additional information
?
-
-
Substrates: other caspases are substrates of caspase-11
Products: -
Products: -
?
additional information
?
-
Substrates: dimerised caspase-11 cannot cleave pro-interleukin-1beta of either species, mouse or human
Products: -
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-
additional information
?
-
Substrates: mouse caspase-11 cannot cleave IL-1beta efficiently
Products: -
Products: -
-
additional information
?
-
Substrates: mouse caspase-11 has an inadequate capacity to cleave pro-IL-1beta. It cleaves gasdermin D more efficiently than pro-IL-1beta
Products: -
Products: -
-
additional information
?
-
-
Substrates: other caspases are substrates of caspase-11
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
Substrates: caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. The expression of caspase-11 is strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide, interferon-Q Q, and tumor necrosis factor-K K in C6 rat glial cells as well as primary astrocytes. Induction of caspase-11 by LPS in astrocytes is mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
gasdermin D + H2O
gasdermin fragment p30 + gasdermin fragment p20
-
Substrates: -
Products: -
Products: -
?
gasdermin D + H2O
N-terminal domain of gasdermin D + C-terminal domain of gasdermin D
Substrates: -
Products: -
Products: -
?
procaspase-3 + H2O
?
-
Substrates: the enzyme is a critical initiator caspase responsible for the activation of caspase-3
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: i.e. TRPC1, plays a role in regulating innate immunity by modulating channel complexes during inflammatory responses
Products: -
Products: -
?
cationic channel subunit transient receptor potential channel 1 + H2O
?
-
Substrates: i.e. TRPC1, plays a role in regulating innate immunity by modulating channel complexes during inflammatory responses
Products: -
Products: -
?
gasdermin D + H2O
?
Substrates: cleavage of gasdermin D (GSDMD) into pore-forming peptides
Products: -
Products: -
?
gasdermin D + H2O
?
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: overexpression induces apoptosis
Products: -
Products: -
?
additional information
?
-
-
Substrates: phenotype of animals deficient in caspase-11: resistant to lipopolysaccharide-induced caspase-1 processing, interleukin-1alpha and interleukin-beta secretion, and endotoxic shock
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is a critical initiator caspase responsible for the activation of caspase-3. The enzyme is an upstream activator of caspase-1. Caspase-11 deficient animals have a reduced number of apoptotic cells and a defect in caspase-3 activation after middle cerebral artery occlusion. The enzyme is A VERY IMPORTANT REGULATOR OF APOPTOSIS
Products: -
Products: -
?
additional information
?
-
-
Substrates: enzyme is involved in cytokine activation
Products: -
Products: -
?
additional information
?
-
-
Substrates: pro-caspase-11 physically interacts with pro-ICE in cells, the expression of casp-11 is essential for activation of ICE. Caspase-11 is a compinent of ICE complex and is required for the activation of ICE. Important role of ICE and caspase-11 in mediating apoptosis in pathological conditions
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in cytokine activation
Products: -
Products: -
?
additional information
?
-
-
Substrates: neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice
Products: -
Products: -
?
additional information
?
-
-
Substrates: C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation
Products: -
Products: -
?
additional information
?
-
-
Substrates: neurotoxicity of 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade
Products: -
Products: -
?
additional information
?
-
-
Substrates: caspase-11 has a regulatory role in ethanol-induced apoptosis. Suppression of caspase-11 expression may be a mechanism by which Scutellariae radix (Chinese herbal medicine) exerts its cytoprotective effect
Products: -
Products: -
?
additional information
?
-
-
Substrates: caspase-11 may be a central regulator of multiple events, including cell migration, cytokine maturation and apoptosis, during inflammation responses. Caspase-11 interacts physically and functionally with actin interacting protein 1, an activator of cofilin-mediated actin depolymerization. Caspase-11 and actin interacting protein 1 work cooperatively to promote cofilin-mediated actin depolymerization
Products: -
Products: -
?
additional information
?
-
-
Substrates: a pathway modulating inflammatory-cell migration involve caspase-11 and actin interacting protein 1
Products: -
Products: -
?
additional information
?
-
-
Substrates: Flightless-I regulates the subcellular distribution of caspase-11 by promoting its localization at the cell leading edge
Products: -
Products: -
?
additional information
?
-
-
Substrates: other caspases are substrates of caspase-11
Products: -
Products: -
?
additional information
?
-
-
Substrates: other caspases are substrates of caspase-11
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme may play a very important role in apoptosis and inflammatory responses and may be an upstream regulator of ICE
Products: -
Products: -
?
additional information
?
-
Substrates: caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. The expression of caspase-11 is strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide, interferon-Q Q, and tumor necrosis factor-K K in C6 rat glial cells as well as primary astrocytes. Induction of caspase-11 by LPS in astrocytes is mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites
Products: -
Products: -
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-adrenaline
inhibits of caspase-11 activation via activated PKA that facilitates caspase-11 phosphorylation
oxidized phospholipids
interact with caspase-11 by binding to the CARD domain, low doses compete with LPS and inhibit caspase-11 activation
-
prostaglandin 2
PGE2, inhibits cpyroptosis and IL-1beta secretion in macrophages
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
lipopolysaccharides
the non-canonical inflammatory pathway-induced pyroptosis is induced by lipopolysaccharide (LPS) on the surface of gram-negative bacteria. This activates caspase-11. LPS to directly enter the cell and activate caspase-11
-
oxidized phospholipids
interact with caspase-11 by binding to the CARD domain, high doses induce caspase-11 oligomerization and activation
-
lipopolysaccharide
LPS, activates caspase-11. Caspase-11 can be activated by binding to internalized LPS
lipopolysaccharide
activation by intracellular LPS leading to caspase-11 oligomerizes into protein complexes and enzymatic cleavage of gasdermin D (GSDMD) into pore-forming peptides. Recognition of LPS by caspase-11 requires guanylate-binding proteins (GBPs). LPS-caspase-11 interaction in the intestinal epithelium is not observed when GBPchr3 KO (knockout) mice, which lack GBP1, 2, 3, 5, and 7, are used as HSCT recipients
LPS
caspase-11 is an essential endogenous receptor for LPS, which binds to the CARD domain of caspase-11 through its lipid A tail moiety to regulate caspase-11 activation, overview
-
LPS
cytosolic LPS induces Casp11 speck formation. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high-molecular-weight complex and activation of caspase-11 catalytic activity
-
additional information
-
activation through dimerization. Signaling pathways involved in caspase-11 activation, overview
-
additional information
-
benzene, increase of caspase-4 expression after 12 days of oral benzene treatment to p53KO mice
-
additional information
-
Bacterial infection triggers caspase-11 activation , and intracellular lipopolysaccharide triggers caspase-11 activation, Toll-like receptor 4 is dispensable for caspase-11 triggering by cytoplasmic lipopolysaccharide, mechanism, detailed overview
-
additional information
-
caspase-11 is activated by a cytosolic sensing mechanism that detects bacterial-derived signals delivered into the host cytosol through the type IV secretion apparatus. Caspase-11 activation by Legionella pneumophila has distinct kinetic and molecular parameters, overview. Caspase-11 activation requires upstream protein(s) capable of sensing a microbial or endogenous danger signal. Caspase-11 requires type I IFN production mediated by TRIF-dependent TLR signaling. And caspase-1 is dispensable for caspase-11-dependent pyroptosis induced by Legionella pneumophila
-
additional information
-
the cholera toxin B subunit and many different Gram-negative bacteria can trigger Caspase-11 activation in vitro. Cytosolic infection of cells with Burkholderia species and cytyosolic mutants of Salmonella typhimurium and Legionella pneumophila trigger the enzyme
-
additional information
-
the adaptor protein TRIF upregulates procaspase-11 expression, and this upregulation is required for caspase-11 processing and activation. Lipopolysaccharide treatment or type I IFN treatment alone does not cause caspase-11-dependent cell death
-
additional information
-
activation through dimerization. Signaling pathways involved in caspase-11 activation, overview
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
cf. caspase-4, EC 3.4.22.57
768451, 770002, 770138, 770172, 770188, 770759, 770782, 771415, 771444, 771849, 772221, 772912, 773810, 773812, 774702, 774708
SwissProt
brenda
cf. caspase-4, EC 3.4.22.57; C57BL/6 and and BALB/c mice
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
enhanced caspase-11 expression in gastric antrum biopsies from ulcer model mice
brenda
intraepithelial lymphocytes, and intestinal lamia propria lymphocytes
brenda
additional information
-
caspase-11 is upregulated in a subpopulation of cells i brain after ischemic injury
brenda
bone marrow-derived macrophages, caspase-11 expression is increased following Helicobacter pylori infection in macrophages
brenda
-
the highest expression levels of murine Casp11 gene are observed in spleens
brenda
additional information
CASP11 is not expressed in healthy tissue unless induced by infection or other pathologic stress
brenda
additional information
mouse caspase-11 is not recruited into inflammasomes
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
caspase-11 is partly localized to the Golgi but not the endoplasmic reticulum
brenda
additional information
-
Flightless-I regulates the subcellular distribution of caspase-11 by promoting its localization at the cell leading edge
-
brenda
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
-
inflammatory caspases all share a similar prodomain at the N-terminus responsible for protein-protein interactions: the caspase activation and recruitment domain (CARD). The genes of the inflammatory caspases are all located adjacent to the Casp1 gene on the mammalian chromosome (chromosome 9 in mouse), forming an inflammatory gene cluster. The close proximity of these genes and the high degree of similarity in the caspase protein structures might explain that the multiple inflammatory caspases arose from amplification of the Casp1 gene locus in the early stages of mammalian evolution
evolution
caspases-4 and -5 are the human orthologues of murine caspase-11, sharing with it 68% and 47% amino acid sequence identity, respectively
evolution
the regions surrounding Lys356 and Lys293 in caspase-4, EC 3.4.22.57, which interact with Glu28 and Asp30 in pro-IL-18, are not conserved in caspase-11. Instead, caspase-11 displays non-charged residues (His352 and Leu289) at these sites
evolution
caspase-11 belongs to the caspase family and is an homologous protein of caspase-1, phylogenetic tree, relationship between caspase-1 and caspase-11 and tertiary structure comparison, overview
evolution
caspase-11, -4, and -5 belong to a family of aspartate-specific cysteine proteases. Their activation requires oligomerization and autoproteolysis. Caspase-11, -4, and -5 contain an N-terminal death fold named caspase recruitment domain (CARD) and a C-terminal catalytic domain
malfunction
-
germline mutation of Casp11 in mouse strain 129 abolishes inflammasome activation by CTB. Strain 129 mice, like Casp11-/- mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
malfunction
-
Casp11-/- knockout mouse strains are resistant to developing lethal sepsis
malfunction
-
all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
malfunction
-
inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells, silencing of caspase-11 protects PC-12 cells from methamphetamine-induced apoptosis. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
malfunction
-
inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
malfunction
-
all Casp1-/- mice also lack caspase-11, due to the generation of the Casp1-/- line in the 129 mouse strain background, which express a mis-spliced and truncated version of the Casp11 messenger RNA
malfunction
-
upon infection with Salmonella typhimurium, the level of pro-interleukin-1beta maturation in bone marrow derived macrophages is reduced in the absence of caspase-11
malfunction
-
defects in the IFN-alpha/beta, but not IFN-gamma, pathways render macrophages severely impaired in processing of caspase-11 following infection with Salmonella typhimurium, EHEC or Citrobacter rodentium, while exogenous IFN-beta rescues caspase-11 processing in Trif-/- macrophages. The absence of the TRIF-IFNAR pathway abolishes both the expression and activation of caspase-11, and treatment of Trif-/- macrophages with IFN-beta or IFN-gamma restores both the precursor and cleaved forms of caspase-11
malfunction
CASP11 deficiency improves clearance of intracellular MRSA in vitro and in vivo. Caspase-11 deficiency allows increased association of MRSA-containing vacuoles with mitochondria. Induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11-/- cells, where mitochondria remain in the vicinity of the bacterium, while in wild-type macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL-1beta, and CASP7, as well as to reduced production of CXCL1/KC. Reduced secretion of IL-1alpha and CXCL1/KC is found only in casp11-/- macrophages, not in caspase1-/- macrophages. Mitochondrial ROS (mtROS) contribute to MRSA clearance in casp11-/- macrophages
malfunction
deletion of the Casp4 gene, which encodes caspase-11, impairs the activation of S1P and SREBP1 as well as alters the expression of genes regulated by SREBP1 in macrophages. Casp4 deletion tends to decrease the upregulation of Srebf1a expression induced by LPS, though the difference does not reach statistical significance. This attenuation of Srebf1a induction in Casp4-/- cells might be due to reduced SREBP1 activity because the Srebf1 promoter is autoregulated by SREBP
malfunction
the increased susceptibility of caspase-11 deficient mice to colitis-associated carcinogenesis (CAC) is associated with decreased STAT1 activity, identifying an anti-tumor role for caspase-11 during CAC via its ability to provide positive enhance STAT1 activation. Casp-11-/- intestinal epithelial cells (IECs) are significantly more susceptible to CAC than wild-type IECs. Colons from CAC-treated Casp-11-/- mice have increased expression of proteins associated with early-stage angiogenesis, suggesting that caspase-11 may have a role in inflammation- and cancer-associated angiogenesis. Caspase-11 activation is significantly impaired in GBPchro3-deficient macrophages
malfunction
the increase in pyroptosis-related protein expression induced by LPS is attenuated with caspase-11 knockout, both in vitro and in vivo. Comparison of pyroptotic cell death of tubular epithelial cells in renal tissue of wild-type mice and caspase-11-/- mice after an LPS challenge. Knockout of caspase-11 improves animal survival after lipopolysaccharide stimulation. Knockout of caspase-11 results in decreased expression of mature IL-1beta in kidney tissue following endotoxemia. Similarly, serum IL-1beta levels are also significantly lower in caspase-11-/- mice than in control mice after LPS challenge
malfunction
caspase-11 knockout mice exhibit attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion after cisplatin treatment. Expression of caspase-11 is significantly increased after cisplatin or hypoxia-reoxygenation treatment. Knockout of GSDMD suppresses the excretion of IL-18 in urine after cisplatin treatment
malfunction
ADP-riboxanation of the Arg310 in caspase-11 blocks autoprocessing of caspase-11 as well as its recognition and cleavage of gasdermin D (GSDMD). ADP-riboxanation of caspase-11 paralyses pyroptosis-mediated defence in Shigella-infected mice. Mutation of ospC3 stimulates caspase-11- and GSDMD-dependent anti-Shigella humoral immunity, generating a vaccine-like protective effect
malfunction
deletion of caspase-11 or Gsdmd, inhibition of LPS-caspase-11 interaction, or neutralizing IL-1alpha uniformly reduces intestinal inflammation, tissue damage, donor T cell expansion, and mortality in allo-HSCT. Importantly, Caspase-11 deficiency does not decrease the graft-versus-leukemia (GVL) activity, which is essential to prevent cancer relapse. Caspase-11 deficiency preserves GVL activity, overview. Loss of caspase-11 renders mice susceptible to Burkholderia pseudomallei, a Gram-negative bacterium. Neutralizing IL-1alpha attenuates GVHD. Overactivation of caspase-11 in endotoxemia or polymicrobial sepsis leads to organ injury and lethality. Dysregulated activation of caspase-11 also contributes to the pathogenesis of age-related macular degeneration
malfunction
wild-type caspase-11 recruits catalytically inactive caspase-11 to speck complexes independently of trans-processing. Catalytically inactive enzyme mutant and non-cleavable enzyme mutant show highly reduced speck formation
malfunction
low-dose Klebsiella pneumoniae infection via the airways to induce a gradually evolving pneumosepsis shows that Casp11-deficient mice display increased bacterial numbers in the lung 12 h and 48 h after inoculation with reduced IL-1alpha levels in bronchoalveolar lavage fluid and increased TNF levels in the lung of Casp11-/- mice at 48 h after inoculation. Caspase-11 deficiency impairs bacterial clearance in the lung, but has no effect on cell death in the lung. Caspase-11 deficiency does not influence lung pathology evoked by Klebsiella
malfunction
prostaglandin 2 (PGE2) inhibits caspase-11-driven IL-1beta production and pyroptosis in a murine model of peritonitis. In vivo inhibition of caspase-11 will effectively attenuate the inflammatory and pyroptotic cascades that occur during ulcer development or perforation
malfunction
binding-deficient CARD-domain point mutants in procaspase-11 do not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections, indicating that the binding site of LPS is located on the CARD domain of procaspase-11. Caspase-11 deficiency does not affect the maturation of IL-1beta and IL-18 following Gram-negative bacterial injection, while the mature IL-1beta and IL-18 in CASP1-/-/CASP11-/- macrophages are significantly reduced
malfunction
mutations in the hydrophobic interface abolish the aggregation of caspase-11 in vitro
malfunction
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the increase in pyroptosis-related protein expression induced by LPS is attenuated with caspase-11 knockout, both in vitro and in vivo. Comparison of pyroptotic cell death of tubular epithelial cells in renal tissue of wild-type mice and caspase-11-/- mice after an LPS challenge. Knockout of caspase-11 improves animal survival after lipopolysaccharide stimulation. Knockout of caspase-11 results in decreased expression of mature IL-1beta in kidney tissue following endotoxemia. Similarly, serum IL-1beta levels are also significantly lower in caspase-11-/- mice than in control mice after LPS challenge
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malfunction
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germline mutation of Casp11 in mouse strain 129 abolishes inflammasome activation by CTB. Strain 129 mice, like Casp11-/- mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
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malfunction
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all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
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malfunction
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low-dose Klebsiella pneumoniae infection via the airways to induce a gradually evolving pneumosepsis shows that Casp11-deficient mice display increased bacterial numbers in the lung 12 h and 48 h after inoculation with reduced IL-1alpha levels in bronchoalveolar lavage fluid and increased TNF levels in the lung of Casp11-/- mice at 48 h after inoculation. Caspase-11 deficiency impairs bacterial clearance in the lung, but has no effect on cell death in the lung. Caspase-11 deficiency does not influence lung pathology evoked by Klebsiella
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malfunction
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inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells, silencing of caspase-11 protects PC-12 cells from methamphetamine-induced apoptosis. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
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metabolism
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Gram-negative bacteria are specifically detected via a surveillance mechanism that involves activation of extracellular receptors such as Toll-like receptors followed by intracellular recognition and activation of pathways such as caspase-11. Extracellular LPS primarily stimulates TLR4, which can serve as a priming signal for expression of inflammasome components. Intracellular LPS can then trigger caspase-11-dependent inflammasome activation in the cytoplasm. Bacterial infection triggers caspase-11 activation and leads to two distinct signals: (i) caspase-1-dependent interleukin-1beta/interleukin-18 secretion and caspase-1-independent pyroptosis
metabolism
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while Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) that aberrantly enter the cytosol trigger Caspase-11, enhancing clearance of S. typhimurium sifA in vivo. This response does not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also trigger Caspase-11, protecting mice from lethal challenge with Burkholderia thailandensis and Burkholderia pseudomallei. Caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens
metabolism
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Gram-negative bacteria and certain pore-forming toxins induce a caspase-11-dependent noncanonical inflammasome that contributes to NLRP3-dependent interleukin-1beta release and also triggers NLRP3- and caspase-1-independent cell death and interleukin-1alpha release
metabolism
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apoptosis is triggered by the initiator caspases, caspase-2, -8, -9, and -10, which subsequently activate the executioner caspases, caspase-3, -6, and -7
metabolism
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apoptosis is triggered by the initiator caspases, caspase-2, -8, -9, and -10, which subsequently activate the executioner caspases, caspase-3, -6, and -7
metabolism
caspase-11 auto-cleavage at the intersubunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of gasdermin D. Macrophages from caspase-11-processing dead KI mice (Casp11Prc D285A/D285A) exhibit defective caspase-11 auto-processing and phenocopy Casp11-/- and caspase-11 enzymatically dead KI (Casp11Enz C254A/C254A) macrophages in attenuating responses to cytoplasmic lipopolysaccharide or Gram-negative bacteria infection. Gasdermin D D276A/D276A KI macrophages also fail to cleave gasdermin D and are hyporesponsive to inflammasome stimuli
metabolism
inhibition of the actin cytoskeleton prevents the dissociation of MRSA-containing phagosomes from mitochondria and leads to bacterial killing. Caspase-11 counteracts mitochondrial ROS-mediated clearance of Staphylococcus aureus in macrophages
metabolism
the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation
metabolism
IRGMs are involved in regulating vacuole/lysosome stability and regulate caspase-11 activity, as well as HMGB1, that binds LPS, entering macrophages/endothelial cells via RAGE-mediated endocytosis, promoting lysosomal rupture and LPS release. Another cytokine that acts as a major regulator of caspase-11 expression is IFN-gamma
metabolism
caspase-11/GSDMD dependent tubule cell pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury
metabolism
ADP-riboxanation of a specific arginine residue in caspase-11/4 is a bacterial virulence mechanism that prevents LPS-induced pyroptosis
metabolism
caspase-11 is a cytosolic LPS receptor that senses various Gram-negative bacteria infections. Caspase-11 enhances GVHD through gasdermin D (GSDMD). GSDMD is a caspase-11 substrate that directly triggers pyroptosis
metabolism
caspases-1 and -11 are inflammatory caspases that are recruited into inflammasome supramolecular organizing centers (SMOCs), which mediate the effector function of the PRR signaling pathway in response to microbial infection or pathologic stimulus, in response to the cytosolic presence of pathogen-derived signals or molecules. Caspase-11 autoprocessing mediates noncanonical inflammasome assembly, overview
metabolism
dimerisation of caspase-4, but not caspase-11, induces the cleavage of human and murine pro-IL-1beta in cells
metabolism
mouse caspase-11 is not recruited into inflammasomes and cannot cleave IL-1beta efficiently, in contrast to human caspase-4 and caspase-5. Human caspase-4 and its mouse homologue caspase-11 possess low activity towards mouse pro-IL-18, whereas human and mouse caspase-1 cleave mouse pro-IL-18 efficiently. Analogous enzymes from dog, lemur, rabbit, and sheep cleave species-matched pro-IL-18 homologues with an efficiency comparable to human caspase-4 cleavage of human pro-IL18
metabolism
inflammatory caspases drive two recognized pyroptotic pathways. Caspase-1 activates the canonical pathway, whereas mouse caspase-4 (also known as caspase-11) and human caspase-4 and caspase-5 initiate the noncanonical pathway. Caspase-4 and caspase-11 are usually considered to be orthologues, even though they may have different biological activities
metabolism
caspase-11, a specific sensor for intracellular lipopolysaccharide recognition, mediates the non-canonical inflammatory pathway of pyroptosis. Pyroptosis is a type of programmed cell death that, along with inflammation, is mainly regulated by two main pathways, cysteinyl aspartate specific proteinase (caspase)-1-induced canonical inflammatory pathway and caspase-11-induced non-canonical inflammatory pathway. The non-canonical inflammatory pathway-induced pyroptosis is a unique immune response in response to Gram-negative bacteria. It is induced by lipopolysaccharide (LPS) on the surface of Gram-negative bacteria. This activates caspase-11 which, in turn, activates a series of downstream proteins eventually forming protein pores on the cell membrane and inducing cell sacrificial processes. Key role caspase-11 plays in the activation of pyroptosis and inflammation. The non-canonical inflammatory pathway is divided into two parts: initiation and excitation, both of which are activated by LPS, regulation of caspase-11 involved non-canonical inflammation, detailed overview
metabolism
murine caspase-11 is the key enzyme of the non-canonical inflammasome pathway that can respond to intracellular LPS and induce pyroptosis. The hydrophobic interface is critical for the cellular activation of the caspase-11 inflammasome
metabolism
although both caspase-1 and caspase-11 can cleave gasdermin D in macrophages and neutrophils, NLRC4-activated caspase-1 triggers pyroptosis in macrophages, but this pathway does not trigger pyroptosis in neutrophils. In contrast, caspase-11 triggers pyroptosis in both macrophages and neutrophils. Cell fates are dictated not simply by the pathogen or inflammasome, but also by how the cell is wired to respond to detection events. In macrophages, caspase-1 is more efficient than caspase-11 at cleaving gasdermin D in response to Burkholderia thailandensis. Caspase-1 alone cannot clear Burkholderia thailandensis infection
metabolism
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while Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) that aberrantly enter the cytosol trigger Caspase-11, enhancing clearance of S. typhimurium sifA in vivo. This response does not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also trigger Caspase-11, protecting mice from lethal challenge with Burkholderia thailandensis and Burkholderia pseudomallei. Caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens
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physiological function
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caspase-11 mediates non-canonical inflammasome activation.Caspase-11 rather than caspase-1 is required for lipopolysaccharide-induced lethality. Interleukin-1beta secretion in response to other bacterial toxins, including adenylcyclase toxin, listeriolysin O toxin, or Clostridium difficile toxin B, is not affected by caspase-11 deficiency. Caspase-11 also is dispensable for NLRP3-dependent IL-1beta secretion in response to monosodium urate, calcium pyrophosphate, or the ionophore nigericin. In contrast, NLRP3- and ASC-dependent IL-1beta secretion from BMDMs infected with live Escherichia coli, Citrobacter rodentium and Vibriae cholerae, requires caspase-11, with or without lipopolysaccharide priming
physiological function
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caspase-11 plays a role in the inflammasome in the cytoplasm. Activation of inflammatory caspases, e.g. caspase-11, leads to the processing and maturation of inflammatory cytokines, such as interleukin-1beta and interleukin-18, as well as a specific form of cell death termed pyroptosis. Caspase-11 can induce cell death and form hetero-complexes with caspase-1. Caspase-11 by itself inefficiently cleaves pro-interleukin-1beta, suggesting early on that caspase-11 might rely on caspase-1 for cytokine maturation. The caspase-11 non-canonical inflammasome plays a significant role in Gram-negative bacterial infections, including Escherichia coli, Citrobacter rodentium, Shigella flexneri, Salmonella typhimurium, Legionella pneumophila, and Burkholderia thailandensis, caspase-11 can restrict the replication of intracellular pathogenic bacteria (Salmonella typhimurium and Burkholderia species)
physiological function
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caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. NLRP3 and ASC are both required for caspase-1 activation through the caspase-11-dependent pathway induced by Legionella pneumophila, caspase-11 is required for NAIP/NLRC4-independent pyroptosis Induced by Legionella pneumophila
physiological function
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caspase-11 is an inflammatory caspase that can also promote interleukin-1beta secretion dependent upon NLRP3, ASC, and Caspase-1. Inflammatory caspase-11 triggers pyroptosis, a form of programmed cell death. The enzyme can be detrimental in inflammatory disease,but has no protective role during infection. Caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria
physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
physiological function
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activated caspase-11 triggers cell death, caspase-11 is essential for the induction of endotoxic shock in vivo
physiological function
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caspase-11-dependent cell death and interleukin-1beta secretion can only be detected in vitro in the absence of a NAIP/NLRC4 stimulus, e.g. flagellin. Caspase-11 is required for the release of the alarmins, interleukin-1alpha and HMGB1. The role of caspase-11 in pro-interleukin-18 and pro-interleukin-1beta maturation is dependent on NLRP3/ASC/CASP1 inflammasomes. Pro-inflammatory caspases play important roles in innate immunity, analysis of mechanisms by which caspase-11 contributes to host defense. Caspase-11 functions and mechanisms of activation, implications for human disease, overview
physiological function
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caspase-11 is required for cofilin phosphorylation. Caspase-11-dependent cell death and interleukin-1beta secretion can only be detected in vitro in the absence of a NAIP/NLRC4 stimulus, e.g. flagellin. Caspase-11 is required for the release of the alarmins, interleukin-1alpha and HMGB1. The role of caspase-11 in pro-interleukin-18 and pro-interleukin-1beta maturation is dependent on NLRP3/ASC/CASP1 inflammasomes. Pro-inflammatory caspases play important roles in innate immunity. Caspase-11 contributes to host defenses against pathogen invasion. Caspase-11 functions and mechanisms of activation, overview
physiological function
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caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide and Gram-negative bacteria. Caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1. Caspase-11 controls the TRPC1-dependent decrease in cytosolic Ca2+ following lipopolysaccharide treatment
physiological function
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mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, importance of this pathway in regulating host defense against intracellular bacterial pathogens. The pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1beta, IL-18, and IL-1alpha, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. Caspase-11 is regulated in response to extracellular stimuli, such as lipopolysaccharide and interferons
physiological function
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mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, importance of this pathway in regulating host defense against intracellular bacterial pathogens. The pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1beta, IL-18, and IL-1alpha, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. Caspase-11 is regulated in response to extracellular stimuli, such as lipopolysaccharide and interferons. Regulation of caspase-11 expression, models of activation, and caspase-11 effector functions, overview. Role of caspase-11 in pyroptosis, caspase-11 directly controls the activation of the effector caspases 3 and 7 of the apoptotic pathway independent of caspase-1
physiological function
caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1beta maturation. Macrophages from gasdermin-/- mice exhibit defective pyroptosis and interleukin-1beta secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. Gasdermin-/- mice are protected from a lethal dose of lipopolysaccharide
physiological function
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gasdermin D fragment p30 that is liberated by caspase-11 forms pores in cellular membrane. p30 is only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharides
physiological function
caspase-1 and caspase-11 display differential roles in response to infection with the fungal pathogen Aspergillus fumigatus. Casp11-/- mice are more susceptible to infection with Aspergillus fumigatus conidia compared with wild-type mice. Casp11-/- mice succumb to infection with a delayed kinetic compared with Casp1Null mice or Casp1-/- Casp11-/- mice. Caspase-11 has no role in the activation of the inflammasome in bone marrow-derived dendritic cells in response to A. fumigatus, but contributes to the host defense against A. fumigatus infection in vivo
physiological function
Casp11-/- mice are highly susceptible to the azoxymethane dextran sulfate sodium model of colitis-associated cancer, compared to their wild-type littermates. Deficient IL-18 production occurs at initial inflammation stages of disease, and IL-1beta production is more significantly impaired in Casp11-/- colons during established colitis-associated cancer. Casp11-/- colons display defective STAT1 activation during disease progression, and IL-1beta signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells
physiological function
caspase-11 deficiency shows the same effect as the combined absence of both caspase-1 and caspase-11 on oviduct pathology. Caspase-11-deficient mice show reduced dilation in both the oviducts and uterus. In the caspase-11-deficient mice, increased chlamydial burdens are observed in the upper genital tract, which correlate with increased CD4 T cell recruitment. There are significantly fewer neutrophils in the oviducts of caspase-11-deficient mice
physiological function
in response to corneal infection with Aspergillus fumigatus, caspase-11-/- mice exhibit the same susceptibility phenotype as IL-1beta-/-, ASC-/-, NLRP3-7-, and caspase-1-/- mice, with impaired neutrophil recruitment to infected corneas and increased hyphal growth. Caspase-11 is required for caspase-1 activation and IL-1eta processing during infection. In vitro, caspase-11 is regulated by the common type I IFN receptor (IFNAR) through JAK-STAT signaling and caspase-11 is required for speck formation and caspase-1 activity
physiological function
inflammatory caspase-11/caspase-4 (CASP11) contributes to non-canonical NLRP3 inflammasome activation and subsequent inflammation. Methicillin-resistant Staphylococcus aureus (MRSA) is capable of persisting within professional phagocytes including macrophages. Caspase-11 counteracts mitochondrial ROS-mediated clearance of Staphylococcus aureus in macrophages, role for CASP11 in facilitating MRSA survival within murine macrophages and in promoting the persistence of Gram-positive bacteria, overview. MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11
physiological function
mouse caspase-11 contributes to SREBP1 activation in the inflammatory response of macrophages, site-1 protease (S1P) is an enzyme that mediates the cleavage and activation of SREBP1. Caspase-11 promotes the processing of S1P - caspase-11 directly associates with S1P and cleaves it at a specific site - and is required for SREBP1 activation in the inflammatory response to LPS. Caspase-11 is required for nuclear translocation of SREBP1 in response to LPS and is important for SREBP1-dependent gene regulation
physiological function
the Classical biotype of Vibrio cholerae triggers caspase-11-dependent non-canonical inflammasome activation in macrophages following CT-mediated cytosolic delivery of LPS. In contrast to the Classical biotype, El Tor Vibrio cholerae induces IL-1beta maturation and secretion in a caspase-11- and CT-independent manner, overview. El Tor Vibrio cholerae (N16961 strain, originally isolated from a cholera patient in Bangladesh) engages the canonical Nlrp3 inflammasome for IL-1b secretion through its accessory hlyA toxin. Vibrio cholerae El Tor biotype does not trigger caspase-11 activation, but instead triggers parallel Nlrp3- and pyrin-dependent pathways toward canonical inflammasome activation to induce IL-1beta-mediated inflammatory responses
physiological function
caspase-11 is an essential endogenous receptor for LPS, which binds to the CARD domain of caspase-11 through its lipid A tail moiety to regulate caspase-11 activation. Caspase-11 upregulation occurs as a result of PAMP and/or cytokine signaling and can be amplified by complement signaling
physiological function
caspase-11 mediates pyroptosis of tubular epithelial cells and septic acute kidney injury. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock. LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. Caspase-11 activation is required for generation of mature IL-1beta and Gsdmd in endotoxic acute kidney injury (AKI), mechanisms by which caspase-11 activation induces AKI, overview
physiological function
caspase-11 is a cysteine protease that promotes cell pyroptosis. Cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury. Inflammation and tubular cell death are the hallmarks of acute kidney injury. Upregulation of caspase-11 by either cisplatin or ischemia-reperfusion leads to cleavage of gasdermin D (GSDMD) into GSDMD-N, which translocates to the plasma membrane, thus triggering cell pyroptosis, and facilitates IL-18 release in primary cultured renal tubular cells. GSDMD is the specific substrate of caspasae-11 and the molecular biomarker of pyroptosis
physiological function
mouse caspase-11 recognizes cytosolic lipopolysaccharide (LPS) to induce pyroptosis by cleaving the pore-forming protein gasdermin D, GSDMD. This non-canonical inflammasome defends against Gram-negative bacteria. But, in contrast to infection with the cytosolic bacterium Burkholderia thailandensis, caspase-11 does not protect mice from infection with Shigella flexneri, which lives freely within the host cytosol where the inflammatory caspases reside. Shigella flexneri evades pyroptosis mediated by caspase-11 using a type III secretion system (T3SS) effector, OspC3. OspC3, but not its paralogues OspC1 and 2, covalently modifies caspase-11. Although it uses the NAD+ donor, this modification is not ADP-ribosylation, but an ADP-riboxanation modification on Arg310 in caspase-11
physiological function
caspase-11 is a cytosolic LPS receptor that senses various Gram-negative bacteria infections. Caspase-11 is the cytosolic receptor for bacterial endotoxin (lipopolysaccharide, LPS). Caspase-11 signaling enhances graft-versus-host disease (GVHD). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) markedly increases the LPS-caspase-11 interaction, leading to the cleavage of gasdermin D (GSDMD). Caspase-11 and GSDMD mediate the release of interleukin-1alpha (IL-1alpha) in allo-HSCT. Upon activation by intracellular LPS, caspase-11 oligomerizes into protein complexes and enzymatically cleaves gasdermin D (GSDMD) into pore-forming peptides, leading to a lytic form of cell death, termed pyroptosis. This process destroys the intracellular niche for microbes and triggers inflammation by releasing alarmins, such as IL-1alpha
physiological function
inflammasomes recruit caspases to undergo proximity-induced autoprocessing into an enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high-molecular-weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. Casp11 catalytic activity and autoprocessing are required for Casp11 to form LPS-induced specks in macrophages and both catalytic activity and autoprocessing are required for Casp11 speck formation downstream of homodimerization in an ectopic expression system, and processing of Casp11 via ectopically expressed TEV protease is sufficient to induce Casp11 speck formation, detailed overview. Caspase-11 autoprocessing mediates noncanonical inflammasome assembly
physiological function
caspase-11 is an intracellular receptor for lipopolysaccharide and regulates pyroptosis, a specific form of inflammatory cell death, which aids in host defense against intracellular gram-negative bacteria. Caspase-11 is also implicated in blood coagulation, local fibrin formation contributes to protective immunity against Klebsiella infection of the lung. Caspase-11 contributes to protective immunity against Klebsiella pneumoniae possibly by activation of blood coagulation in the lung. Role of caspase-11 in host defense during Klebsiella pneumoniae-evoked pneumonia and sepsis, overview
physiological function
the noncanonical inflammasome is a signalling complex critical for cell defence against cytosolic Gram-negative bacteria. A key step in the human noncanonical inflammasome pathway involves unleashing the proteolytic activity of caspase-4 within this complex. The enzyme directly cleaves GSDMD, which is consistent with established functions for murine caspase-11 in initiating cell death independently of caspase-1. Caspase-11, the murine counterpart of caspase-4, acquires protease activity within the noncanonical inflammasome by forming a dimer that self-cleaves at D285 to cleave gasdermin D (GSDMD)
physiological function
murine caspase-11 is an essential mediator of sepsis. Primary murine macrophages infected with Helicobacter pylori upregulate caspase-1 (the orthologue of human caspase-4, EC 3.4.22.57), activate caspase-1, and secrete IL-1beta. Pathological role of caspase-4/11 in peptic ulcer disease, caspase-11 contributes to the inflammation and mucosal damage that occur during ulcer formation. Perforated peptic ulcers can lead to peritonitis and, subsequently, sepsis. Caspase-11-mediated pyroptosis causes the release of damage-associated molecular patterns (DAMPs) and ATP, which can subsequently activate NLRP3 and caspase-1, which will serve to further boost pyroptosis levels
physiological function
in contrast to the human enzyme, mouse caspase-11 does not function as a sensor and effector that mediates cleavage and release of IL-18, and is not involved in canonical inflammasomes
physiological function
caspase-11 contributes to in ipsilateral dorsal horn of spinal cord, and consequently to pain hypersensitivity in the later phase of complete Freund's adjuvant (CFA)-induced pain of mice. Persistent neuroinflammation and central sensitization play important roles in the pathogenesis of chronic pain disease. Caspase-11 is a critical modulator of inflammation of the central nervous system
physiological function
caspase-11 is a specific sensor for intracellular lipopolysaccharide recognition. Key role caspase-11 plays in the activation of pyroptosis and inflammation. When caspase-11 is activated, it induces the downstream substrate GSDM D to cleave into the N terminal and C terminal domains, with the N-terminal domain on the cell membrane. Cleavage removes the C-terminal fragment (GSDMD-CT). The N-terminal oligomerizes in membranes to form pores that triggers pyroptosis
physiological function
sensing of cytoplasmic lipopolysaccharide (LPS) results in the self-cleavage and activation of caspase-11. The activated caspase can then drive the canonical inflammasome pathway to induce pyroptosis. The activation of caspase-11 is involved in the development of inflammatory responses, such as lethal sepsis, making it an important target for drug development
physiological function
macrophages detect Burkholderia thailandensis via NLRC4, triggering the release of interleukin (IL)-18 and driving an essential interferon (IFN)-gamma response that primes caspase-11. The neutrophil caspase-11 is essential to defend against the cytosol-invasive bacterium. Caspase-11 can cleave gasdermin D to cause pyroptosis, eliminating intracellular replication niches. The IFN-gamma-producing cells are a mixture of natural killer (NK) and T cells. In neutrophils, caspase-1 (EC 3.4.22.36) and caspase-11 activation lead to gasdermin D cleavage, but only caspase-11 activation leads to pyroptosis that is necessary for clearance of this cytosol-invasive pathogen in vivo. The caspase-11 inflammasome monitors for lipopolysaccharide (LPS) contamination as a marker for the virulence trait of cytosolic invasion. Cellular detection mechanism, overview. Multiple lymphocyte populations respond to Burkholderia thailandensis infection. Absolute requirement for caspase-11 and gasdermin D in neutrophils during Burkholderia thailandensis infection in mice
physiological function
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caspase-11 mediates pyroptosis of tubular epithelial cells and septic acute kidney injury. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock. LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. Caspase-11 activation is required for generation of mature IL-1beta and Gsdmd in endotoxic acute kidney injury (AKI), mechanisms by which caspase-11 activation induces AKI, overview
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physiological function
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caspase-11 mediates non-canonical inflammasome activation.Caspase-11 rather than caspase-1 is required for lipopolysaccharide-induced lethality. Interleukin-1beta secretion in response to other bacterial toxins, including adenylcyclase toxin, listeriolysin O toxin, or Clostridium difficile toxin B, is not affected by caspase-11 deficiency. Caspase-11 also is dispensable for NLRP3-dependent IL-1beta secretion in response to monosodium urate, calcium pyrophosphate, or the ionophore nigericin. In contrast, NLRP3- and ASC-dependent IL-1beta secretion from BMDMs infected with live Escherichia coli, Citrobacter rodentium and Vibriae cholerae, requires caspase-11, with or without lipopolysaccharide priming
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physiological function
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caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. NLRP3 and ASC are both required for caspase-1 activation through the caspase-11-dependent pathway induced by Legionella pneumophila, caspase-11 is required for NAIP/NLRC4-independent pyroptosis Induced by Legionella pneumophila
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physiological function
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caspase-11 is an inflammatory caspase that can also promote interleukin-1beta secretion dependent upon NLRP3, ASC, and Caspase-1. Inflammatory caspase-11 triggers pyroptosis, a form of programmed cell death. The enzyme can be detrimental in inflammatory disease,but has no protective role during infection. Caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria
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physiological function
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caspase-11 is an intracellular receptor for lipopolysaccharide and regulates pyroptosis, a specific form of inflammatory cell death, which aids in host defense against intracellular gram-negative bacteria. Caspase-11 is also implicated in blood coagulation, local fibrin formation contributes to protective immunity against Klebsiella infection of the lung. Caspase-11 contributes to protective immunity against Klebsiella pneumoniae possibly by activation of blood coagulation in the lung. Role of caspase-11 in host defense during Klebsiella pneumoniae-evoked pneumonia and sepsis, overview
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physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
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physiological function
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caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide and Gram-negative bacteria. Caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1. Caspase-11 controls the TRPC1-dependent decrease in cytosolic Ca2+ following lipopolysaccharide treatment
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physiological function
-
the Classical biotype of Vibrio cholerae triggers caspase-11-dependent non-canonical inflammasome activation in macrophages following CT-mediated cytosolic delivery of LPS. In contrast to the Classical biotype, El Tor Vibrio cholerae induces IL-1beta maturation and secretion in a caspase-11- and CT-independent manner, overview. El Tor Vibrio cholerae (N16961 strain, originally isolated from a cholera patient in Bangladesh) engages the canonical Nlrp3 inflammasome for IL-1b secretion through its accessory hlyA toxin. Vibrio cholerae El Tor biotype does not trigger caspase-11 activation, but instead triggers parallel Nlrp3- and pyrin-dependent pathways toward canonical inflammasome activation to induce IL-1beta-mediated inflammatory responses
-
additional information
-
caspase-1, -2, -4, -9, and -11 have particularly long pro-domains that contain either death effector domains (DED) or caspase recruitment domains (CARD), which are thought to confer specificity of activation since they mediate interactions with other DED- and CARD-containing adaptor proteins. Association with these adaptor proteins likely nucleates caspases, increasing their local concentration. This nucleation can favor activation through dimerization
additional information
-
caspase-11 cooperatively interacts with actin-interacting protein to activate cofilin-dependent actin depolymerization leading to increased splenocyte migration, caspase-11-mediated actin depolymerization appears to be independent of its enzymatic activity. Caspase-1, -2, -4, -9, and -11 have particularly long pro-domains that contain either death effector domains (DED) or caspase recruitment domains (CARD), which are thought to confer specificity of activation since they mediate interactions with other DED- and CARD-containing adaptor proteins. Association with these adaptor proteins likely nucleates caspases, increasing their local concentration. This nucleation can favor activation through dimerization
additional information
the enzymatic activity of caspases is ruled by a dominant specificity for aspartic acid containing proteins and a cysteine side chain that acts as a catalytic nucleophile to employ peptide cleavage. Caspase-11 structure analysis and comparison
additional information
morphological changes of programmed cell death, detailed overview
additional information
caspase-11-mediated gasdermin D (GSDMD) cleavage and cell death are dependent on the hydrophobic surface on H1 2 of CARD. The hydrophobic interface is critical for the cellular activation of the caspase-11 inflammasome
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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). CASP4_MOUSE
373
0
42742
Swiss-Prot
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
additional information
dimer
caspases are expressed in most cells as inactive monomeric zymogens (pro-caspases), requiring processing and heterodimerization to facilitate their activation
dimer
inducible dimerization activates caspase-11. Formation of a functional Casp11 inflammasome supramolecular organizing center (SMOC) involves additional steps beyond inducible dimerization, overview
additional information
caspase-11 catalytic activity and autoprocessing at the interdomain linker are required for spontaneous caspase-11 oligomerization in recombinant HEK293T cells
additional information
caspase-11 contains two components, an N-terminal caspase recruitment domain (CARD) and a C-terminal catalytic domain. The MBP-tagged caspase-11 CARD domain tetramerizes in solution. An extensive hydrophobic interface formed by the H1-2 helix mediates homotypic CARD interactions. The CARD mediates caspase oligomerization through CARD CARD interaction. The CARD of caspase-11 is essential for LPS-induced pyroptosis. Overall crystal structure of the caspase-11 CARD, overview
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
L-adrenaline binds ADRA2B, activating PKA. Activated PKA facilitates caspase-11 phosphorylation
proteolytic modification
side-chain modification
arginine ADP-riboxanase OspC3 catalyses ADP-riboxanation on arginine 310 in caspase-11. A 17-Da loss occurs on the phosphoribosylated arginine caused by non-specific pyrophosphohydrolase, NUDT16, which removes an AMP from OspC3-modified caspase-11. Deamino-NAD+, biotin-NAD+, epsilon-NAD+ or nicotinamide guanine dinucleotide (NGD+) allow modifications that preserve the mass difference between the cognate analogue and NAD+ confirming the transfer of ADPR to caspase-11 with Nam being the leaving group. OspC3 modifies Arg310 of caspase-11 by two steps. First, the arginine Ndelta (rather than Nomega) performs nucleophilic substitution of the Nam in NAD+. Second, the ribosyl-2'-OH of ADPR initiates a deamination to remove one Nomega, forming an oxazolidine ring. Although OspC3(D177A) mutant-modified caspase-11 is sensitive to ADP-ribosylarginine hydrolase (ADPRH), wild-type OspC3-catalysed ADP-riboxanation resists demodification by ADPRH and other known host ADP-ribosylhydrolases. OspC3 blocks LPS-induced caspase-11 autoprocessing
proteolytic modification
-
the enzyme requires activation through proteolytic cleavage
proteolytic modification
-
TRIF is required for the processing of procaspase-11 into the cleaved caspase-11 forms
proteolytic modification
-
the adaptor protein TRIF upregulates procaspase-11 expression, and this upregulation is required for caspase-11 processing and activation
proteolytic modification
-
TRIF is required for the processing of procaspase-11 into the cleaved caspase-11 forms. IFNs or lipopolyaccharides alone are not sufficient to trigger caspase-11 processing, but an unidentified factor derived from live Gram-negative bacteria is required, which is likely a mechanism to ensure that inflammatory responses do not proceed in the absence of active infection
proteolytic modification
LPS activates pro-caspase-11 cleavage and activation of caspase-11 functions
proteolytic modification
caspases are expressed in most cells as inactive monomeric zymogens (pro-caspases), requiring processing and heterodimerization to facilitate their activation. Caspase-11 auto-proteolysis is essential for its activation and the subsequent regulation of downstream events. Caspase-11 activation, induced experimentally via its overexpression or cytoplasmic LPS stimulation, induces two autoproteolysis events, resulting in the removal of the N-terminal CARD domain from the large subunit and separating the large and small catalytic domains
proteolytic modification
caspase-11 performs LPS-induced autoprocessing to activate itself. Mutations of Arg310 inhibit infection- or LPS-induced pyroptosis
proteolytic modification
the enzyme needs to be self-cleaved to become activated, autoprocessing at the interdomain linker. Enzyme mutant D285A is non-cleavable. Caspase-11 autoprocessing mediates noncanonical inflammasome assembly
proteolytic modification
caspase-11, the murine counterpart of caspase-4, acquires protease activity within the noncanonical inflammasome by forming a dimer that self-cleaves at D285 to cleave GSDMD
proteolytic modification
the enzyme is produced as procaspase-11 and activated by proteolytic cleavage. After transcription and translation, a large amount of procaspase-11 and proIL-1beta, proIL-18 is generated and distributed in the cytoplasm. LPS binds with procaspase-11, initiate procaspase-11 oligomerization and form mature/activated caspase-11
proteolytic modification
tetrameric aggregation of caspase-11 is thought to promote the autoprocessing and activation of caspase-11, activation mechanism of caspase-11, overview. The tetramerization of the N-terminal CARD prevents catalytic domain autoinhibition, leading to the caspase-11 activation. The hydrophobic interface is critical for the cellular activation of the caspase-11 inflammasome
proteolytic modification
-
the enzyme requires activation through proteolytic cleavage
proteolytic modification
-
the enzyme requires activation through proteolytic cleavage
-
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant caspase-11 CARD, hanging drop vapor diffusion method, the well solution contains 2.4 M ammonium sulfate and 5% isopropanol, 18 C, 1 week, X-ray diffraction structure determination and analysis at 2.8 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C254A
C254A/D285A
site-directed mutagenesis, an inactive, IDL-uncleavable Casp11 mutant
C254A/K19E
site-directed mutagenesis, mutations on the helix H1 2 located in the N-terminal side of CARD domain
D285A
K19E
site-directed mutagenesis, the charge mutation positions in the middle of helix H1 2
V13A/L14A/L17A/V21A
site-directed mutagenesis, VLLV-caspase-11 mutant, mutations on the helix H1 2 located in the N-terminal side of CARD domain destroy the hydrophobic interactions
additional information
C254A
site-directed mutagenesis, OspC3 also co-immunoprecipitated with inactive p20- and-p10-unprocessed caspase-11
C254A
site-directed mutagenesis, the catalytically inactive mutant shows highly reduced speck formation, catalytically deficient Casp11 lacks the ability to oligomerize autonomously
D285A
mutation disrupts the processing site in the linker region between the large and small subunits of caspase-11
D285A
site-directed mutagenesis, mutation of the IDL cleavage site, the non-cleavable mutant shows highly reduced speck formation
additional information
-
targeting Casp11 exon 5 for deletion in C57BL/6 embryonic stem cells. Strain 129 mice, like Casp11-/- mutant mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
additional information
-
generation of Casp11-/- knockout mice, overview. The common mouse knockout strategy is to inject genetically targeted 129-derived ES cells into host C57BL/6 blastocysts and then backcross the chimera with other strains, commonly C57BL/6, for over 10 generations
additional information
-
generation of Casp11-/- mice, all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
additional information
-
all Casp1-/- mice also lack caspase-11, due to the generation of the Casp1-/- line in the 129 mouse strain background, which express a mis-spliced and truncated version of the Casp11 messenger RNA
additional information
-
recombination and segregation of the nonfunctional Casp11 gene away from the Casp1-/- locus is nearly impossible because Casp1 and Casp11 occur only about 1500 bp apart on chromosome 9 in mice
additional information
-
all Casp1-/- mouse strains generated from 129 embryonic stem cells also lack caspase-11 due to a 5-bp deletion in the caspase-11 locus that causes loss of the catalytic domain. As the caspase-11 and caspase-1 loci are located physically close together, the mutations do not segregate during backcrossing, leading to double mutant mice
additional information
generation of caspase11-/- mice and caspase1/11-/- mice
additional information
generation of Casp-11-/- mice. Cisplatin-induced tubular dilation, loss of brush border, cast formation, and cell lysis in tubules are significantly ameliorated in Casp-11-/- mice. The level of urinary IL-18 is significantly suppressed in Casp-11-/- mice compared with wild-type mice after cisplatin treatment. Deletion of caspase-11 suppresses the infiltration of macrophages and neutrophils in cisplatin-induced acute kidney injury
additional information
lipopolysaccharide (LPS)-caspase-11 interaction enhances graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Caspase-11 enhances donor T cell expansion in allo-HSCT
additional information
recombinant expression of fluorescently labeled Casp11 in macrophages reveals that cytosolic LPS induces Casp11 speck formation in transformed HEK-293T cells. Both catalytic activity and autoprocessing are required for Casp11 speck formation in an ectopic expression system, and processing of Casp11 via ectopically expressed TEV protease is sufficient to induce Casp11 speck formation. Wild-type caspase-11 recruits catalytically inactive caspase-11 to speck complexes independently of trans-processing
additional information
generation of Casp11-/- mice. Caspase-11 deficiency impairs bacterial clearance in the lung, phenotype, overview
additional information
generation of bone marrow-derived Casp-/- macrophages
additional information
structure-based engineering of caspase-11 to generate a model of a hypothetical caspase-11-pro-IL-18 complex. this complex, critical exosite residues Trp263 and Arg265 (corresponding to Trp267 and Arg269 in caspase-4) fit into the hydrophobic pocket in pro-IL-18. Introducing caspase-4-specific mutations at His352 and Leu289 in caspase-11 increases its ability to cleave pro-IL-18 in vitro to a level similar to caspase-4
additional information
complete Freund's adjuvant (CFA) injection significantly decreases the hind paw mechanical pain threshold in Von Frey test on 1-7 days after injection and increases the caspase-11 level of ipsilateral dorsal horn of spinal cord on day 2 and day 5 after injection. Compared to wild-type mice, caspase-11-/- mice show significantly higher mechanical pain threshold in the later phase of CFA-induced pain, but not in the early phase, and have no significant difference in 5% formalin induced licking and flinching behavior. In addition, the microglial activation, and the mRNA levels of caspase-1 and IL-18 in the spinal cord of caspase-11-/- mice restore to baseline on the day 5 after CFA injection, but not in wild-type mice. Phenotypes, overview
additional information
mutations of the helix H1-2 hydrophobic residues abolish the tetramerization of MBP-tagged CARD in solution and fail to induce pyroptosis in cells. The mutations abolish the aggregation of caspase-11 CARD and prohibit the self-cleavage of caspase-11
additional information
-
targeting Casp11 exon 5 for deletion in C57BL/6 embryonic stem cells. Strain 129 mice, like Casp11-/- mutant mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
-
additional information
-
generation of Casp11-/- mice, all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
-
additional information
-
generation of caspase11-/- mice and caspase1/11-/- mice
-
additional information
-
generation of Casp11-/- mice. Caspase-11 deficiency impairs bacterial clearance in the lung, phenotype, overview
-
additional information
-
enzyme downregulation by siRNA and shRNA sequence targeting caspase-11
additional information
-
enzyme downregulation by siRNA and shRNA sequence targeting caspase-11
-
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant MBP-tagged caspase-11 CARD domain, recombinant EGFP-tagged wild-type and mutant enzymes from HEK-293T cells by affinity chromatography and gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene CASP11, overexpression of FLAG-tagged enzyme in HEK-293T cells, co-expression with HA-tagged cationic channel subunit transient receptor potential channel 1, i.e. TRPC1, subunits p10 and p20 of caspase-11, but not caspase recruitment domain (CARD) alone, is co-immunoprecipitated with TRPC1. FLAG-tagged caspase-11 is able to co-immunoprecipitate independently with HA-tagged TRPC1 N-terminal alone, the N-terminal domain with the transmembrane domain, and the transmembrane domain with the C-terminal domain, but not with the central transmembrane domain alone
-
gene CASP4, recombinant expression of 2xFLAG-tagged wild-type and mutant enzymes in HEK-293T cells
gene CASP4, recombinant expression of wild-type and mutant enzymes in HEK-293T cells
gene Casp4, the murine inflammatory caspases genes are located on syntenic regions of mouse chromosome 9A1
recombinant expression of isolated wild-type and mutant N-terminally MBP-tagged and C-terminally His6-tagged caspase-11 CARD domains in Escherichia coli strains Rosetta and BL21(DE3), recombinant expression of C-terminally EGFP-tagged wild-type and mutant enzymes in HEK-293T cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
bacterial lipopolysaccharide stimulation of caspase-11 expression in several mouse tissues, particularly in the spleen
-
CASP11 is induced by infection or other pathologic stress. Upregulation of CASP11 in cell lysates of infected wild-type as well as casp1-/- macrophages
caspase-11 expression is increased following Helicobacter pylori strain NCTC11638 infection in macrophages. Prostaglandins (PGs) inhibit caspase-11 upregulation, IL-1beta production, and pyroptosis in mice
caspase-11 expression is stimulated by TLR signaling, IL-1 signaling, mitochondrial DNA damage, the complement pathway, and IFN signaling involving receptors TLR2, TLR3, TLR4, TLR5, ILR9, IL-1R, mtDNA, C3aR, IFNAR, and IFNGR: The responsible stimulators of the receptors are Pam3CSK4, dsRNA, LPS, flagellin, CpG-rich DNA, interleukin-1beta, c-Gas-STING, C3a, and IFNalpha/beta. Involved pathways and regulation mechanisms, detailed overview
cytosolic infection of cells with Burkholderia species and cytyosolic mutants of Salmonella typhimurium and Legionella pneumophila trigger the enzyme
increase in pyroptosis-related protein expression is induced by LPS
induction of caspase-11 is dependent on NF-kappaB. PARP-1 participates in the activation of caspase-11 promoter as a coactivator of NF-kappaB. Lipopolysaccharide induce the enzyme expression
-
induction of procaspase-11 expression is delayed in Myd88-/- macrophages infected with DELTAFlag Salmonella typhimurium, although procaspase-11 processing itself remains intact
-
Lipopolysaccharide treatment or type I IFN treatment alone does not cause caspase-11-dependent cell death
-
mRNA expression of Casp4, which encodes caspase-11, starts to increase at 1 h and reaches its peak at 6 h after treatment with LPS
poly(ADP-ribose) polymerase-1, PARP-1, regulates the expression of caspase-11 following lipopolysaccharide stimulation. PARP-1 is recruited to the caspase-11 promoter region containing predicted nuclear factor (NF)-kappaB-binding sites, but PARP-1 enzymatic activity is not required for the caspase-11 upregulation. PARP-1 can regulate the induction of caspase-11 at a transcriptional level. PARP-1 participates in the activation of caspase-11 promoter as a coactivator of NF-kappaB
-
TLR 2 promotes the expression of caspase-11 by activating the NF-kappaB-transduction of the Myd88. TLR 3 also promotes the expression of caspase-11 by inducing the production of IFN-alpha/beta (IFN-I). After transcription and translation, a large amount of procaspase-11 and proIL-1beta, proIL-18 is generated and distributed in the cytoplasm
type I IFN signaling is sufficient to induce caspase-11 upregulation and processing. The adaptor protein TRIF upregulates procaspase-11 expression, and this upregulation is required for caspase-11 processing and activation
-
cytosolic infection of cells with Burkholderia species and cytyosolic mutants of Salmonella typhimurium and Legionella pneumophila trigger the enzyme
-
cytosolic infection of cells with Burkholderia species and cytyosolic mutants of Salmonella typhimurium and Legionella pneumophila trigger the enzyme
-
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
caspase-11 has a regulatory role in ethanol-induced apoptosis. Suppression of caspase-11 may be a mechanism by which Scutellariae radix (Chineses herbal medicine) exerts its cytoprotective effect
medicine
gasdermin D (GSDMD)-dependent pyroptosis mediated by caspase-11 might be a target in preventing the loss of renal tubular epithelial cells and inflammation in acute kidney injury (AKI)
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REF.
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TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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279
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Mus musculus
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176
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Mus musculus
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24
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Mus musculus
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181
321-333
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Mus musculus
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9
245-246
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Mus musculus
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9
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Mus musculus
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Positive Role of CCAAT/Enhancer-Binding Protein Homologous Protein, a Transcription Factor Involved in the Endoplasmic Reticulum Stress Response in the Development of Colitis
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795-803
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Mus musculus
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Suyama, K.; Ohmuraya, M.; Hirota, M.; Ozaki, N.; Ida, S.; Endo, M.; Araki, K.; Gotoh, T.; Baba, H.; Yamamura, K.
C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis
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367
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87
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180
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28
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Rattus norvegicus (Q91XW7)
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29
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408
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Kayagaki, N.; Warming, S.; Lamkanfi, M.; Vande Walle, L.; Louie, S.; Dong, J.; Newton, K.; Qu, Y.; Liu, J.; Heldens, S.; Zhang, J.; Lee, W.P.; Roose-Girma, M.; Dixit, V.M.
Non-canonical inflammasome activation targets caspase-11
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Revisiting caspase-11 function in host defense
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14
9-14
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Homo sapiens, Mus musculus
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6
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Vigano, E.; Mortellaro, A.
Caspase-11: the driving factor for noncanonical inflammasomes
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43
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Homo sapiens, Mus musculus
brenda
Stowe, I.; Lee, B.; Kayagaki, N.
Caspase-11: arming the guards against bacterial infection
Immunol. Rev.
265
75-84
2015
Mus musculus
brenda
Case, C.L.; Kohler, L.J.; Lima, J.B.; Strowig, T.; de Zoete, M.R.; Flavell, R.A.; Zamboni, D.S.; Roy, C.R.
Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila
Proc. Natl. Acad. Sci. USA
110
1851-1856
2013
Mus musculus, Mus musculus C57BL/6
brenda
Aachoui, Y.; Leaf, I.A.; Hagar, J.A.; Fontana, M.F.; Campos, C.G.; Zak, D.E.; Tan, M.H.; Cotter, P.A.; Vance, R.E.; Aderem, A.; Miao, E.A.
Caspase-11 protects against bacteria that escape the vacuole
Science
339
975-978
2013
Mus musculus, Mus musculus C57BL/6
brenda
Huang, W.; Xie, W.B.; Qiao, D.; Qiu, P.; Huang, E.; Li, B.; Chen, C.; Liu, C.; Wang, Q.; Lin, Z.; Wang, H.
Caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis
Toxicol. Sci.
145
68-79
2015
Rattus norvegicus, Homo sapiens, Rattus norvegicus Sprague Dawley
brenda
Allen, J.; Gyorke, C.E.; Tripathy, M.K.; Zhang, Y.; Lovett, A.; Montgomery, S.A.; Nagarajan, U.M.
Caspase-11 contributes to oviduct pathology during genital Chlamydia infection in mice
Infect. Immun.
87
e00262
2019
Mus musculus (P70343), Mus musculus
brenda
Lee, B.L.; Stowe, I.B.; Gupta, A.; Kornfeld, O.S.; Roose-Girma, M.; Anderson, K.; Warming, S.; Zhang, J.; Lee, W.P.; Kayagaki, N.
Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation
J. Exp. Med.
215
2279-2288
2018
Mus musculus (P70343), Mus musculus
brenda
Sun, Y.; Abbondante, S.; Karmakar, M.; De Jesus Carrion, S.; Che, C.; Hise, A.; Pearlman, E.
Neutrophil caspase-11 is required for cleavage of caspase-1 and secretion of IL-1beta in Aspergillus fumigatus infection
J. Immunol.
201
2767-2775
2018
Mus musculus (P70343)
brenda
Kayagaki, N.; Stowe, I.B.; Lee, B.L.; ORourke, K.; Anderson, K.; Warming, S.; Cuellar, T.; Haley, B.; Roose-Girma, M.; Phung, Q.T.; Liu, P.S.; Lill, J.R.; Li, H.; Wu, J.; Kummerfeld, S.; Zhang, J.; Lee, W.P.; Snipas, S.J.; Salvesen, G.S.; Morris, L.X.; Fitzgerald, L.; Zhang, Y.; Bertram, E.M.; Goodnow, C.C.; Di, D.i.x.
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Nature
526
666-671
2015
Mus musculus (P70343), Mus musculus
brenda
Flood, B.; Manils, J.; Nulty, C.; Flis, E.; Kenealy, S.; Barber, G.; Fay, J.; Mills, K.H.G.; Kay, E.W.; Creagh, E.M.
Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis
Oncogene
38
2658-2674
2019
Mus musculus (P70343), Mus musculus
brenda
Aglietti, R.A.; Estevez, A.; Gupta, A.; Ramirez, M.G.; Liu, P.S.; Kayagaki, N.; Ciferri, C.; Dixit, V.M.; Dueber, E.C.
GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes
Proc. Natl. Acad. Sci. USA
113
7858-7863
2016
Homo sapiens
brenda
Man, S.M.; Karki, R.; Briard, B.; Burton, A.; Gingras, S.; Pelletier, S.; Kanneganti, T.D.
Differential roles of caspase-1 and caspase-11 in infection and inflammation
Sci. Rep.
7
45126
2017
Mus musculus (P70343), Mus musculus
brenda
Perlee, D.; de Beer, R.; Florquin, S.; van der Poll, T.; van't Veer, C.; de Vos, A.F.
Caspase-11 contributes to pulmonary host defense against Klebsiella pneumoniae and local activation of coagulation
Am. J. Physiol. Lung Cell Mol. Physiol.
319
L105-L114
2020
Mus musculus (P70343), Mus musculus C57BL6 (P70343)
brenda
Liu, M.; Cao, W.; Qin, X.; Tong, J.; Wu, X.; Cheng, Y.
Caspase-11 contributes to pain hypersensitivity in the later phase of CFA-induced pain of mice
Brain Res.
1801
148172
2023
Mus musculus (P70343)
brenda
Huang, X.; Feng, Y.; Xiong, G.; Whyte, S.; Duan, J.; Yang, Y.; Wang, K.; Yang, S.; Geng, Y.; Ou, Y.; Chen, D.
Caspase-11, a specific sensor for intracellular lipopolysaccharide recognition, mediates the non-canonical inflammatory pathway of pyroptosis
Cell Biosci.
9
31
2019
Mus musculus (P70343)
brenda
Liu, M.; Zhou, K.; Xu, Z.; Ma, H.; Cao, X.; Yin, X.; Zeng, W.; Zahid, A.; Fu, S.; Ni, K.; Ye, X.; Zhou, Y.; Bai, L.; Zhou, R.; Jin, T.
Crystal structure of caspase-11 CARD provides insights into caspase-11 activation
Cell Discov.
6
70
2020
Mus musculus (P70343)
brenda
Kovacs, S.B.; Oh, C.; Maltez, V.I.; McGlaughon, B.D.; Verma, A.; Miao, E.A.; Aachoui, Y.
Neutrophil caspase-11 isessential to defend against a cytosol-invasive bacterium
Cell Rep.
32
107967
2020
Mus musculus (P70343)
brenda
Akuma, D.C.; Wodzanowski, K.A.; Schwartz Wertman, R.; Exconde, P.M.; Vazquez Marrero, V.R.; Odunze, C.E.; Grubaugh, D.; Shin, S.; Taabazuing, C.; Brodsky, I.E.
Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS
eLife
13
e83725
2024
Mus musculus (P70343)
brenda
Krause, K.; Daily, K.; Estfanous, S.; Hamilton, K.; Badr, A.; Abu Khweek, A.; Hegazi, R.; Anne, M.N.; Klamer, B.; Zhang, X.; Gavrilin, M.A.; Pancholi, V.; Amer, A.O.
Caspase-11 counteracts mitochondrial ROS-mediated clearance of Staphylococcus aureus in macrophages
EMBO Rep.
20
e48109
2019
Mus musculus (P70343)
brenda
Mamantopoulos, M.; Frising, U.C.; Asaoka, T.; van Loo, G.; Lamkanfi, M.; Wullaert, A.
El Tor biotype Vibrio cholerae activates the caspase-11-independent canonical Nlrp3 and pyrin inflammasomes
Front. Immunol.
10
2463
2019
Mus musculus (P70343), Mus musculus C57BL/6J (P70343)
brenda
Cheng, Y.; Manabe, I.; Hayakawa, S.; Endo, Y.; Oishi, Y.
Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages
Front. Immunol.
14
1009973
2023
Mus musculus (P70343)
brenda
Zaslona, Z.; Flis, E.; Nulty, C.; Kearney, J.; Fitzgerald, R.; Douglas, A.R.; McNamara, D.; Smith, S.; ONeill, L.A.J.; Creagh, E.M.
Caspase-4 a therapeutic target for peptic ulcer disease
ImmunoHorizons
4
627-633
2020
Mus musculus (P70343)
brenda
Agnew, A.; Nulty, C.; Creagh, E.M.
Regulation, activation and function of caspase-11 during health and disease
Int. J. Mol. Sci.
22
1506
2021
Mus musculus (P70343)
brenda
Bibo-Verdugo, B.; Joglekar, I.; Karadi Giridhar, M.N.; Ramirez, M.L.; Snipas, S.J.; Clark, A.C.; Poreba, M.; Salvesen, G.S.
Resurrection of an ancient inflammatory locus reveals switch to caspase-1 specificity on a caspase-4 scaffold
J. Biol. Chem.
298
101931
2022
Mus musculus (P70343)
brenda
Ye, Z.; Zhang, L.; Li, R.; Dong, W.; Liu, S.; Li, Z.; Liang, H.; Wang, L.; Shi, W.; Malik, A.B.; Cheng, K.T.; Liang, X.
Caspase-11 mediates pyroptosis of tubular epithelial cells and septic acute kidney injury
Kidney Blood Press. Res.
44
465-478
2019
Mus musculus (P70343), Mus musculus C57BL (P70343)
brenda
Miao, N.; Yin, F.; Xie, H.; Wang, Y.; Xu, Y.; Shen, Y.; Xu, D.; Yin, J.; Wang, B.; Zhou, Z.; Cheng, Q.; Chen, P.; Xue, H.; Zhou, L.; Liu, J.; Wang, X.; Zhang, W.; Lu, L.
The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury
Kidney Int.
96
1105-1120
2019
Mus musculus (P70343)
brenda
Chan, A.H.; Burgener, S.S.; Vezyrgiannis, K.; Wang, X.; Acklam, J.; Von Pein, J.B.; Pizzuto, M.; Labzin, L.I.; Boucher, D.; Schroder, K.
Caspase-4 dimerisation and D289 auto-processing elicit an interleukin-1beta-converting enzyme
Life Sci. Alliance
6
e202301908
2023
Mus musculus (P70343)
brenda
Lu, Y.; Meng, R.; Wang, X.; Xu, Y.; Tang, Y.; Wu, J.; Xue, Q.; Yu, S.; Duan, M.; Shan, D.; Wang, Q.; Wang, H.; Billiar, T.R.; Xiao, X.; Chen, F.; Lu, B.
Caspase-11 signaling enhances graft-versus-host disease
Nat. Commun.
10
4044
2019
Mus musculus (P70343)
brenda
Li, Z.; Liu, W.; Fu, J.; Cheng, S.; Xu, Y.; Wang, Z.; Liu, X.; Shi, X.; Liu, Y.; Qi, X.; Liu, X.; Ding, J.; Shao, F.
Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11
Nature
599
290-295
2021
Mus musculus (P70343)
brenda
Devant, P.; Dong, Y.; Mintseris, J.; Ma, W.; Gygi, S.P.; Wu, H.; Kagan, J.C.
Structural insights into cytokine cleavage by inflammatory caspase-4
Nature
624
451-459
2023
Mus musculus (P70343)
brenda
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