Genomes and Genes
Gene Symbol: Gzmb
Description: granzyme B
Alias: AI553453, CCP-1/C11, CCP1, Ctla-1, Ctla1, GZB, granzyme B(G,H), cytotoxic cell protease 1, fragmentin-2
- Pham C, MacIvor D, Hug B, Heusel J, Ley T. Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci U S A. 1996;93:13090-5 pubmed..These results suggest that the PGK-Neo cassette can interact productively with locus control regions and thereby disrupt normal interactions between local and long-distance regulatory regions within a tissue-specific domain. ..
- Wang Y, Lobigs M, Lee E, Mullbacher A. Exocytosis and Fas mediated cytolytic mechanisms exert protection from West Nile virus induced encephalitis in mice. Immunol Cell Biol. 2004;82:170-3 pubmed..Virus-host immune interactions have to be assessed individually and cannot be generalized. ..
- van Dommelen S, Sumaria N, Schreiber R, Scalzo A, Smyth M, Degli Esposti M. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. Immunity. 2006;25:835-48 pubmed..Viral titres increased markedly in both Prf1(-/-) and Gzma(-/-)Gzmb(-/-) mice, but Gzma(-/-)Gzmb(-/-) mice recovered and survived infection, whereas Prf1(-/-) mice did not...
- Lovo E, Zhang M, Wang L, Ashton Rickardt P. Serine protease inhibitor 6 is required to protect dendritic cells from the kiss of death. J Immunol. 2012;188:1057-63 pubmed publisher..We conclude that the negative regulation of DC priming of CD8 T lymphocyte immunity by CTL killing is mitigated by the physiological inhibition of GrB by Spi6. ..
- Heusel J, Scarpati E, Jenkins N, Gilbert D, Copeland N, Shapiro S, et al. Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene. Blood. 1993;81:1614-23 pubmed..Expression of this gene is detected only in the bone marrow and is restricted to a small population of early myeloid cells. These findings are consistent with the identification of the gene encoding murine CG. ..
- Graubert T, Dipersio J, Russell J, Ley T. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J Clin Invest. 1997;100:904-11 pubmed..In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation. ..
- Simon M, Hausmann M, Tran T, Ebnet K, Tschopp J, ThaHla R, et al. In vitro- and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J Exp Med. 1997;186:1781-6 pubmedGranzyme (gzm) A and gzmB have been implicated in Fas-independent nucleolytic and cytolytic processes exerted by cytotoxic T (Tc) cells, but the underlying mechanism(s) remains unclear...
- Smyth M, Street S, Trapani J. Cutting edge: granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol. 2003;171:515-8 pubmed
- Balkow S, Kersten A, Tran T, Stehle T, Grosse P, Museteanu C, et al. Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol. 2001;75:8781-91 pubmed
- Susanto O, Stewart S, Voskoboinik I, Brasacchio D, Hagn M, Ellis S, et al. Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. Cell Death Differ. 2013;20:1183-93 pubmed publisher..This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes. ..
- Kelso A, Costelloe E, Johnson B, Groves P, Buttigieg K, Fitzpatrick D. The genes for perforin, granzymes A-C and IFN-gamma are differentially expressed in single CD8(+) T cells during primary activation. Int Immunol. 2002;14:605-13 pubmed
- Riera L, Gariglio M, Valente G, Mullbacher A, Museteanu C, Landolfo S, et al. Murine cytomegalovirus replication in salivary glands is controlled by both perforin and granzymes during acute infection. Eur J Immunol. 2000;30:1350-5 pubmed
- Veugelers K, Motyka B, Goping I, Shostak I, Sawchuk T, Bleackley R. Granule-mediated killing by granzyme B and perforin requires a mannose 6-phosphate receptor and is augmented by cell surface heparan sulfate. Mol Biol Cell. 2006;17:623-33 pubmed..We therefore propose the model that under physiological conditions serglycin-bound granzyme B is critically endocytosed by a mannose 6-phosphate receptor, and receptor binding is enhanced by cell surface heparan sulfate. ..
- Devadas S, Das J, Liu C, Zhang L, Roberts A, Pan Z, et al. Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity. 2006;25:237-47 pubmed..GrB-deficient mice exhibited increased susceptibility to allergen-induced asthma. Thus, GrB plays a critical role in the TCR-ICD of Th2 cells. ..
- Gondek D, Devries V, Nowak E, Lu L, Bennett K, Scott Z, et al. Transplantation survival is maintained by granzyme B+ regulatory cells and adaptive regulatory T cells. J Immunol. 2008;181:4752-60 pubmedGranzyme B (GZB) has been implicated as an effector mechanism in regulatory T cells (T(reg)) suppression. In a model of T(reg)-dependent graft tolerance, it is shown that GZB- deficient mice are unable to establish long-term tolerance...
- Estella E, McKenzie M, Catterall T, Sutton V, Bird P, Trapani J, et al. Granzyme B-mediated death of pancreatic beta-cells requires the proapoptotic BH3-only molecule bid. Diabetes. 2006;55:2212-9 pubmed..Our data suggest that Bid cleavage by granzyme B precedes mitochondrial disruption and apoptosis in pancreatic islets. ..
- Phillips T, Opferman J, Shah R, Liu N, Froelich C, Ashton Rickardt P. A role for the granzyme B inhibitor serine protease inhibitor 6 in CD8+ memory cell homeostasis. J Immunol. 2004;173:3801-9 pubmed..We propose that expression of protective molecules, like Spi6, serves to shield metabolically active CD8+ memory T cells from their own effector molecules. ..
- Freishtat R, Natale J, Benton A, Cohen J, Sharron M, Wiles A, et al. Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. Am J Respir Crit Care Med. 2009;179:467-73 pubmed publisher..Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy. ..
- Dressel R, Raja S, Honing S, Seidler T, Froelich C, von Figura K, et al. Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells. J Biol Chem. 2004;279:20200-10 pubmed..In conclusion, these results strongly argue against an Mpr300- or Mpr46-dependent pathway of granzyme-mediated killing and provide new insight in the internalization of monomeric and complexed granzyme B. ..
- Grossman W, Revell P, Lu Z, Johnson H, Bredemeyer A, Ley T. The orphan granzymes of humans and mice. Curr Opin Immunol. 2003;15:544-52 pubmed..Although the functions of these orphan granzymes have yet to be fully established, initial data suggests their importance in both immune and nonimmune cells. ..
- Hiebert P, Granville D. Granzyme B in injury, inflammation, and repair. Trends Mol Med. 2012;18:732-41 pubmed publisher..The present review focuses on the emerging evidence for the involvement of granzyme B in chronic inflammation, impaired wound healing, and age-related skin fragility. ..
- Brunet J, Dosseto M, Denizot F, Mattei M, Clark W, Haqqi T, et al. The inducible cytotoxic T-lymphocyte-associated gene transcript CTLA-1 sequence and gene localization to mouse chromosome 14. Nature. 1986;322:268-71 pubmed
- Kaiserman D, Bird C, Sun J, Matthews A, Ung K, Whisstock J, et al. The major human and mouse granzymes are structurally and functionally divergent. J Cell Biol. 2006;175:619-30 pubmed..These results demonstrate that even "orthologous" granzymes have species-specific functions, having evolved in distinct environments that pose different challenges. ..
- Thia K, Trapani J. The granzyme B gene is highly polymorphic in wild mice but essentially invariant in common inbred laboratory strains. Tissue Antigens. 2007;70:198-204 pubmed..evolutionary basis for this observation, we sequenced the exons and flanking intronic sequences of the mouse Gzmb gene from a variety of inbred laboratory strains and wild mice...
- Alsharifi M, Lobigs M, Simon M, Kersten A, Muller K, Koskinen A, et al. NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol. 2006;36:887-96 pubmed..This is the first study illustrating an NK cell-mediated immunopathological outcome to an acute viral infection. ..
- Lobe C, Finlay B, Paranchych W, Paetkau V, Bleackley R. Novel serine proteases encoded by two cytotoxic T lymphocyte-specific genes. Science. 1986;232:858-61 pubmed..Moreover, it has sequence characteristics thought to occur only in rat mast cell protease type II. These results are in accord with the view that a protease cascade plays a key role in cytotoxic T-cell activation. ..
- Waterhouse N, Sutton V, Sedelies K, Ciccone A, Jenkins M, Turner S, et al. Cytotoxic T lymphocyte-induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis. J Cell Biol. 2006;173:133-44 pubmed..Therefore, CTLs from granzyme AB(-/-) mice induce target cell death by a unique mechanism that is distinct from both perforin lysis and apoptosis. ..
- Revell P, Grossman W, Thomas D, Cao X, Behl R, Ratner J, et al. Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J Immunol. 2005;174:2124-31 pubmedAlthough the functions of granzyme A (GzmA) and GzmB are well-defined, a number of orphan granzymes of unknown function are also expressed in cytotoxic lymphocytes...
- Cao X, Cai S, Fehniger T, Song J, Collins L, Piwnica Worms D, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27:635-46 pubmed..Granzyme B and perforin are therefore relevant for Treg cell-mediated suppression of tumor clearance in vivo...
- Regner M, Pavlinovic L, Koskinen A, Young N, Trapani J, Mullbacher A. Cutting edge: rapid and efficient in vivo cytotoxicity by cytotoxic T cells is independent of granzymes A and B. J Immunol. 2009;183:37-40 pubmed publisher..Specific target cell elimination occurred with similar kinetics in both spleen and lymph nodes. Thus, neither gzmA nor gzmB are required for rapid and efficient in vivo cytotoxicity by Tc cells.
- Zhang M, Park S, Wang Y, Shah R, Liu N, Murmann A, et al. Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules. Immunity. 2006;24:451-61 pubmed..Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules. ..
- Sutton V, Waterhouse N, Browne K, Sedelies K, Ciccone A, Anthony D, et al. Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis. J Cell Biol. 2007;176:425-33 pubmed..Cathepsin C deficiency also results in considerably milder immune deficiency than perforin or granzyme A/B deficiency. ..
- Cullen S, Adrain C, Lüthi A, Duriez P, Martin S. Human and murine granzyme B exhibit divergent substrate preferences. J Cell Biol. 2007;176:435-44 pubmedThe cytotoxic lymphocyte protease granzyme B (GzmB) can promote apoptosis through direct processing and activation of members of the caspase family...
- Adrain C, Murphy B, Martin S. Molecular ordering of the caspase activation cascade initiated by the cytotoxic T lymphocyte/natural killer (CTL/NK) protease granzyme B. J Biol Chem. 2005;280:4663-73 pubmed..These studies indicate that granzyme B targets a highly restricted range of substrates and orchestrates cellular demolition largely through activation of caspase-3. ..
- Anthony D, Andrews D, Chow M, Watt S, House C, Akira S, et al. A role for granzyme M in TLR4-driven inflammation and endotoxicosis. J Immunol. 2010;185:1794-803 pubmed publisher..Most importantly, these data demonstrate that granzymes should no longer be considered solely as mediators of apoptosis, but additionally as potential key regulators of inflammation. ..
- Rizzitelli A, Meuter S, Vega Ramos J, Bird C, Mintern J, Mangan M, et al. Serpinb9 (Spi6)-deficient mice are impaired in dendritic cell-mediated antigen cross-presentation. Immunol Cell Biol. 2012;90:841-51 pubmed publisher..Although the core processing machinery is unaffected, Sb9-deficient DC appear to process antigen faster. Our results point to a novel, GrB-independent role for Sb9 in DC cross-priming. ..
- Afonina I, Tynan G, Logue S, Cullen S, Bots M, LÃ¼thi A, et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1Î±. Mol Cell. 2011;44:265-78 pubmed publisher..Thus, IL-1Î± processing by multiple immune-related proteases, including granzyme B, acts as a switch to enhance the proinflammatory properties of this cytokine. ..
- Casciola Rosen L, Garcia Calvo M, Bull H, Becker J, Hines T, Thornberry N, et al. Mouse and human granzyme B have distinct tetrapeptide specificities and abilities to recruit the bid pathway. J Biol Chem. 2007;282:4545-52 pubmed
- Shresta S, Graubert T, Thomas D, Raptis S, Ley T. Granzyme A initiates an alternative pathway for granule-mediated apoptosis. Immunity. 1999;10:595-605 pubmed..We show in this report that perforin-dependent, gzmB-independent cytotoxicity is caused by gzmA (or tightly linked genes)...
- Mullbacher A, Waring P, Tha Hla R, Tran T, Chin S, Stehle T, et al. Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes. Proc Natl Acad Sci U S A. 1999;96:13950-5 pubmed..In this paper, we show that mice lacking both granzyme A (gzmA) and granzyme B (gzmB), which are, beside perforin, key constituents of cytolytic vesicles, are as incapable as are perforin-deficient ..
- Heusel J, Wesselschmidt R, Shresta S, Russell J, Ley T. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell. 1994;76:977-87 pubmed..We conclude that gzm B serves a critical and nonredundant role for the rapid induction of target cell DNA fragmentation and apoptosis by alloreactive cytotoxic T lymphocytes. ..
- Pardo J, Wallich R, Martin P, Urban C, Rongvaux A, Flavell R, et al. Granzyme B-induced cell death exerted by ex vivo CTL: discriminating requirements for cell death and some of its signs. Cell Death Differ. 2008;15:567-79 pubmedGranzyme B (gzmB) of cytotoxic T lymphocytes (CTL) is essential for recovery from intracellular pathogens, but the molecular basis of its action is still unresolved...
- Sutton V, Estella E, Li C, Chen M, Thomas H, Kay T, et al. A critical role for granzyme B, in addition to perforin and TNFalpha, in alloreactive CTL-induced mouse pancreatic beta cell death. Transplantation. 2006;81:146-54 pubmed
- Pardo J, Balkow S, Anel A, Simon M. The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells. Eur J Immunol. 2002;32:1980-5 pubmed..molecules or transfected cytolytic effector cells have suggested that both, granzyme A (gzmA) and granzyme B (gzmB), similarly contribute to CTL-mediatedand perforin (perf)-dependent apoptotic nuclear damage (DNA fragmentation) in ..
- Pardo J, Balkow S, Anel A, Simon M. Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol. 2002;32:2881-7 pubmed..However, recent work using mice deficient in either gzmA, gzmB or both gzm suggested that only perf but neither of the two gzm are critical for tumor surveillance by CTL or NK ..
- Fehniger T, Cai S, Cao X, Bredemeyer A, Presti R, French A, et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity. 2007;26:798-811 pubmed..These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation. ..
- Jenne D, Rey C, Masson D, Stanley K, Herz J, Plaetinck G, et al. cDNA cloning of granzyme C, a granule-associated serine protease of cytolytic T lymphocytes. J Immunol. 1988;140:318-23 pubmed..The amino acids lining the specificity pocket are well conserved between granzyme B, C, and rat mast cell protease II, but not granzyme A, suggesting a similar general specificity of these three proteases. ..
- Joeckel L, Wallich R, Martin P, Sánchez Martínez D, Weber F, Martin S, et al. Mouse granzyme K has pro-inflammatory potential. Cell Death Differ. 2011;18:1112-9 pubmed publisher..Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK. ..
- Hiebert P, Wu D, Granville D. Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice. Cell Death Differ. 2013;20:1404-14 pubmed publisher..Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-..
- Martin P, Pardo J, Schill N, Jöckel L, Berg M, Froelich C, et al. Granzyme B-induced and caspase 3-dependent cleavage of gelsolin by mouse cytotoxic T cells modifies cytoskeleton dynamics. J Biol Chem. 2010;285:18918-27 pubmed publisher..The present study shows that isolated mouse gzmB cleaves the actin-severing mouse protein, cytoplasmic gelsolin (c-gelsolin) in vitro...
- Sebbagh M, Hamelin J, Bertoglio J, Solary E, Bréard J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med. 2005;201:465-71 pubmed..During granule-induced cell death, ROCK II cleavage by grB would overcome, for this apoptotic feature, the consequences of deficient caspase activation that may occur in virus-infected or malignant target cells. ..
- Chen M, Felix K, Wang J. Immune regulation through mitochondrion-dependent dendritic cell death induced by T regulatory cells. J Immunol. 2011;187:5684-92 pubmed publisher..Bax- and Bak-dependent cell death mechanisms help to maintain DC homeostasis and contribute to the regulation of T cell activation and the suppression of autoimmunity. ..
- Murphy M, Moult J, Bleackley R, Gershenfeld H, Weissman I, James M. Comparative molecular model building of two serine proteinases from cytotoxic T lymphocytes. Proteins. 1988;4:190-204 pubmed..The derived amino acid sequences, coding for cytotoxic cell protease 1 (CCP1) and Hannuka factor (HF) are highly homologous to members of the serine proteinase family...
- Duggan B, Cabilio N, Dickie P, Witmer J, Goping I, Underhill D, et al. A novel lineage-specific hypersensitive site is essential for position independent granzyme B expression in transgenic mice. Biochem Biophys Res Commun. 2008;368:357-63 pubmed publisher..Deletion of HS2 resulted in a 10-fold reduction in expression. This is the first report of a major distal regulatory element in the control of granzyme B transcription. ..
- Lykens J, Terrell C, Zoller E, Risma K, Jordan M. Perforin is a critical physiologic regulator of T-cell activation. Blood. 2011;118:618-26 pubmed publisher..We conclude that perforin-dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation. ..
- Ceci J, Kingsley D, Silan C, Copeland N, Jenkins N. An interspecific backcross linkage map of the proximal half of mouse chromosome 14. Genomics. 1990;6:673-8 pubmed..This interspecific backcross map will be valuable for establishing linkage relationships of additional loci to mouse chromosome 14. ..
- Wilson J, Prow N, Schroder W, Ellis J, Cumming H, Gearing L, et al. RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation. PLoS Pathog. 2017;13:e1006155 pubmed publisher..Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. ClinicalTrials.gov NCT00281294. ..