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evolution
neutrophil serine proteases, proteinase 3 and human neutrophil elastase, share high sequence similarity, but have different substrate specificities and functions
evolution
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presence of an elastase in Xenopus closely related to hPR-3 indicates a relatively early appearance of these enzymes during vertebrate evolution, sequence comparisons and phylogenetic analysis of the hematopoietic serine proteases, overview
evolution
presence of an elastase in Xenopus closely related to hPR-3 indicates a relatively early appearance of these enzymes during vertebrate evolution, sequence comparisons and phylogenetic analysis of the hematopoietic serine proteases, overview
malfunction
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in mice lacking neutrophil serine PR3 (DPPI-/- mice), inhibition of caspase 1 activity results in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. Dual blockade of both PR3 and caspase 1 leads to protection against cartilage and bone destruction. Deficiency of PR3 in combination with inhibition of caspase 1 does not reduce the joint swelling in streptococcal cell wall-induced acute arthritis
malfunction
excessive release of proteases mediates tissue damage
malfunction
overexpression of proteinase 3 in chronic myeloid leukemia induces apoptosis of high-affinity PR1-specific T cells, leading to deletional tolerance and leukemia outgrowth
malfunction
phospholipid scramblase 1 (PLSCR1) knockdown using siRNA not only prevents PR3 membrane expression but also increases the rate of apoptotic cell clearance by macrophages
malfunction
ratios between neutrophil serine proteases and their natural inhibitor are altered in non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes when compared to healthy controls
metabolism
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pro-PR3 interacts with CD63 upon heterologous co-expression in COS cells but endogenous interaction is not detected although cell surface proPR3 and CD63 are co-endocytosed in myelomonocytic cells. Cell surface pro-PR3 turns over more rapidly than cell surface CD63 consistent with processing/degradation of the pro-protease but recycling of CD63. Colocalization of proPR3 and CD63 with clathrin and Rab 7 suggests trafficking through coated vesicles and late endosomes. Blocking the C-terminus of pro-PR3 by creating a fusion with FK506 binding protein does not inhibit endosomal re-uptake of proPR3
metabolism
the enzyme is a target for chronic inflammatory diseases
metabolism
histone demethylase JMJD3 (EC 1.14.11.68) regulates the expression of neutrophil membrane proteinase 3 (mPR3) in lipopolysaccharide-stimulated neutrophils during the early inflammatory response in sepsis. JMJD3 regulates the expression of mPR3 by changing the level of trimethylated histone H3 on Lys27 (H3K27me3) in LPS-stimulated neutrophils
metabolism
increased proteinase 3 and neutrophil elastase (EC 3.4.21.37) plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, potential role for the neutrophil serine proteases (NSPs), proteinase-3 (PR3) and neutrophil elastase (NE), in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). Circulating levels of NSPs associate with obesity-related metabolic disorders
metabolism
PR3 concentration in azurophilic granules is approximately 3 times higher than that of human neutrophil elastase and cathepsin G, and the enzyme is less susceptible to inhibition by endogenous serine protease inhibitors correlates with PR3 implication in various pathological processes
physiological function
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69-year-old Caucasian female presenting initially with an isolated parotid abscess and only subsequently developing nasal, paranasal sinus and respiratory symptoms, shows anti-neutrophil cytoplasmic antibodies against proteinase 3 titres
physiological function
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activation of IL-1beta in a manner independent of caspase 1 is especially apparent in the acute phase of inflammation, characterized by a predominantly neutrophilic infiltrate that serves as a source for PR3
physiological function
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all c-ANCA-positive samples (diagnosed Wegener granulomatosis) show a significant increase of PR3 activity
physiological function
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almost complete absence of anti-neutrophil cytoplasmic antibody (cANCA) binding to rhesus monkey PR3
physiological function
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anti-neutrophil cytoplasmic antibodies (cANCAs) from Wegeners granulomatosis patients at least in part recognize similar surface structures as do mouse antibodies and compete with the binding of alpha1-protease inhibitor to PR3
physiological function
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caspase 1-independent processing of IL-1beta occurs in arthritis by serine proteases such as PR3
physiological function
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gibbon PR3 shows an intermediate anti-neutrophil cytoplasmic antibody (cANCA) binding pattern, whereas some anti-PR3 mouse antibodies and some patient sera recognize the antigen. The cANCAs from Wegeners granulomatosis patients at least in part recognize similar surface structures as do mouse antibodies and compete with the binding of alpha1-protease inhibitor to PR3
physiological function
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involvement in the regulation of intracellular functions such as proliferation or apoptosis. Its membrane expression is a risk factor in chronic inflammatory diseases. PR3 is the preferred target antigen in Wegener's granulomatosis. Colocalization of PR3 with the integrin CD11b/CD18 (b2 integrin), the Fcgamma receptor FcgRIIIb and the p22phox subunit of cytochrome b558 in the membrane. Both PR3 and phospholipid scramblase 1 are associated within the same protein complex
physiological function
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is a major anti-neutrophil cytoplasmic autoantibodies (ANCA)-antigen in Wegener's granulomatosis. Abnormally expressed membrane-bound PR3 is involved in the development and severity of Wegener's granulomatosis. Strong correlation of the percentages of membrane-bound PR3 high neutrophils between monozygotic twins but not in dizygotic twins. PR3 is externalized during neutrophil apoptosis independent of degranulation, which is mediated by phospholipid scramblase 1. CD177-deficient neutrophils also can be activated by PR3-anti-neutrophil cytoplasmic autoantibodies in vitro, thus CD177 is not necessary for this signaling
physiological function
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macaque PR3 shows nearly no reactivity to anti-neutrophil cytoplasmic antibodies (cANCAs)
physiological function
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neutrophil activation by PR3 antineutrophil cytoplasmic autoantibodies (ANCAs). CD177 may be a determinant of membrane expression of PR3 and, as such, influences the potential of neutrophils to be activated by PR3 ANCAs
physiological function
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neutrophil-derived PR3 can induce kallikrein-independent activation of the kinin pathway
physiological function
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occurrence of anti-neutrophil-cytoplasmic antibodies (ANCA) directed against proteinase-3 is a hallmark of Wegeners granulomatosis. Association of anti-PR3 titers and disease activity, which remains controversial. PR3 antigen elicits strong Th1-responses via dendritic cell maturation and subsequent antigen presentation to T-cells. Initial immune response in autoimmunity is directed against complementary PR3, resulting in the formation of antibodies against complementary PR3 (idiotypic response). Later on, an anti-idiotypic response against anti-complementary PR3 antibodies evolves. The antibodies formed during this anti-idiotypic response react to the sense autoantigen PR3. ANCA produced by granuloma-resident B cells bind to primed neutrophils that express PR3 on their surface. Genetic sequences complementary to human PR3 gene are detected in pathogens like Staphylococcus aureus, Ross River virus and Entamoeba histolytica. complementary PR3 transcripts are absent from healthy controls, PR3-ANCA-negative or lupus patients. Complementary PR3 mRNA is present in leukocytes of PR3-ANCA patients
physiological function
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PRTN3-specific CD4+ T-cells precursors are part of normal human T-cell repertoires. T-cell precursors specific for various PRTN3 epitopes can be activated when properly stimulated. T-cell clones proliferate in response to peptides PRTN358 (GTLIHPSFVLTAAHALRDI), PRTN3216 (IDSFVIWGAATRLFPDFF), PRTN3235 (RVALYVDWIRSTLRR), and PRTN3241 (DWIRSTLRRVEAKGRP). T-cell clones specific for these four PRTN3 peptides strongly respond to autologous peripheral blood mononuclear cells in the presence of corresponding peptides. Only PRTN3235 is recognized by CD4+ T-cells as a naturally processed HLAclass-II-epitope. PRTN3235-specific CD4+ T-cells do not proliferate vigorously to stimulation with PRTN3-positive leukemia cell. PRTN3235 is able to induce T-cell responses in individuals with diverse DR genotypes
physiological function
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significant Pr3 activity at the surface of activated neutrophils but not at the surface of quiescent neutrophils whatever the constitutive expression. Permanent presence of inactive Pr3 at the surface of quiescent neutrophils, which may explain why Pr3 is a major target of anti-neutrophil cytoplasmic antibodies, whose binding activates neutrophils and triggers inflammation, as in Wegener granulomatosis
physiological function
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PR3 membrane insertion appears to be pivotal for its proinflammatory activities, such as extracellular proteolysis and impairment of apoptotic cell clearance, but also for myeloid cell proliferation
physiological function
proteinase 3 is a major autoimmune target in systemic vasculitis. Proteinase 3 is an abundant serine protease of neutrophil granules and a major target of PR3 antineutrophil cytoplasmic autoantibodies in granulomatosis with polyangiitis. Some of the enzyme synthesized by promyelocytes in the bone marrow escape the targeting to granules and occur on the plasma membrane of naive and primed neutrophils. This membrane-associated PR3 antigen may represent pro-PR3, mature PR3, or both forms
physiological function
the enzyme is involved in granulomatosis with polyangiitis, anti-neutrophil cytoplasmic antibodies with proteinase 3 specificity are not implicated in the pathogenesis
physiological function
effect of membrane proteinase 3-expressing polymorphonuclear neutrophils (PMN) and acute myeloid leukemia (AML) blasts on the proliferation of CD4 and CD8 T cells in vitro, overview. mP3-expressing PMN significantly inhibits autologous healthy donor T-cell proliferation but does not affect cytokine production in activated T-cells. This effect requires cell proximity and is abrogated by proteinase 3 blockade. This inhibition requires proteinase 3 enzyme activity. The suppression is not reversed by either the addition of catalase or the inhibition of arginase I. PMN inhibit T cell proliferation in a cell contact-dependent manner. In addition to proteinase 3 blockade, anti-low density lipoprotein receptor-related protein 1 (LRP1) Ab also restores T cells' capacity to proliferate. Dose-dependent inhibition of T-cell proliferation by mP3-expressing acute myeloid leukemia blasts
physiological function
membrane proteinase 3 (mPR3) expression on neutrophils plays a critical role in pro-inflammatory cytokine production. Plasma cytokine (interleukin-1beta and TNF-alpha) levels are increased in patients with sepsis exhibiting high mPR3 expression
physiological function
proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Proteinase 3 also is a phosphatidylserine-binding protein that affects the production and function of microvesicles. The interaction is dependent on the hydrophobic patch responsible for membrane anchorage. PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. The binding of PR3 to phosphatidylserine, a major component of microvesicles, leads to reduced production of microvesicles in PR3-expressing cells. PR3-expressing cells produce significantly fewer microvesicles during both activation and apoptosis, and this reduction is dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored microvesicle production. Activation-evoked microvesicles from PR3-expressing cells induce a significantly larger respiratory burst in human neutrophils compared with control microvesicles, while microvesicles generated during apoptosis inhibit the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hamper this inhibition. Microvesicles generated from neutrophils expressing membrane PR3 may potentiate oxidative damage of endothelial cells and promote the systemic inflammation observed in this disease. PR3 hampers the ability of apoptosis-induced microvesicles to inhibit a respiratory burst in neutrophils. During apoptosis, membrane-bound PR3 serves as a 'don't eat me' signal. It is co-externalized with phosphatidylserine (PS) via its association with phospholipid scramblase 1 (PLSCR1), a protein facilitating membrane flip-flop
physiological function
the neutrophil serine protease proteinase-3 (PR3) is able to process interleukin-1beta to its bioactive form independently of caspase-1-NLRP3 inflammasome complex
physiological function
the neutrophilic serine protease proteinase 3 (PR3) is involved in inflammation and immune response and is a therapeutic target for a variety of infectious and inflammatory diseases
physiological function
the physiological role of PR3 is seen either inside the phagocytic vacuoles or externally where PR3 is engaged in processing of proinflammatory cytokines, receptors, heat shock proteins and other host proteins which after PR3-mediated hydrolysis lead to the generation of antibacterial peptides (e.g. cathelicidin hCAP-18). PR3 is capable of hydrolyzing several extracellular matrix proteins including collagen, elastin, fibronectin and laminin causing the inflammation and tissue injury. PR3 is also known as the antigen in granulomatosis with polyangiitis (GPA), a chronic inflammatory condition that triggers autoimmune response resulting in the production of antineutrophil cytoplasmic antibodies (ANCA). As the binding of ANCA activates neutrophils and therefore increases the level of cell surface PR3, the protein is directly involved in the pathogenesis of the disease
additional information
proteinase 3 is an abundant serine protease with high similarity to neutrophil elastase
additional information
enzyme-microvesicle interaction analysis by surface plasmon resonance spectroscopy. Molecular modeling
additional information
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enzyme-microvesicle interaction analysis by surface plasmon resonance spectroscopy. Molecular modeling
additional information
similarly to azurocidin or CatG, PR3 can also act via the non-catalytic mechanism