Disease relevance of Gzma

• Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes [1].
• We show that the genes for tumor necrosis factor alpha and granzyme A, a serine protease associated with cytoplasmic granules of cytotoxic cells, are expressed during the development of spontaneous diabetes mellitus in the nonobese diabetic mouse [1].
• For this purpose we have analyzed the response of mice that lack Fas as well as granzyme A (gzmA) and gzmB (FasxgzmAxB(-/-)) to infection with lymphocytic choriomeningitis virus (LCMV) [2].
• Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies [3].
• Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia [4].

Psychiatry related information on Gzma

• Interleukin 2 increased granzyme A protein expression independent of alcohol consumption; however, this increase was associated with decreased enzyme activity [5].

High impact information on Gzma

• The serine esterase affinity label diisopropyl fluorophosphate reacts strongly with granzymes A and D, to a lesser extent with B, E, F, G, and H, and not at all with C and F. For granzymes A and D, synthetic substrates have been found [6].
• Isolation and characterization of a serine esterase from cytolytic T cell granules [7].
• The serine esterase activity is secreted by lymphocytes that have been stimulated with the calcium ionophore A23187 [7].
• The two proteins, referred to as serine esterases 1 and 2 (SE 1 and SE 2), migrate with Mr of 34-36 kd and 28-30 kd, respectively, under reducing conditions [7].
• Cytotoxic T lymphocytes and lymphocytes with NK-like activity contain a serine esterase activity which has been localized to their cytoplasmic granules by cytochemistry and subcellular fractionation studies [7].

Chemical compound and disease context of Gzma

• In the CD8+ RT-1.3G3 hybridoma, which is nonlytic and specific for the HIV-1 envelope glycoprotein, c-fos but not granzyme A mRNA was induced by 45 min poststimulation, and no granzyme A mRNA was detectable at any time [8].
• The effect of two synthetic serine esterase inhibitors, N-alpha-dansyl(p-guanidino)phenylalaninepiperidine hydrochloride (I 2581) and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (D-Phe-Pro-Arg-CH2Cl), on bone resorption in organ cultured mouse calvaria from neonatal mice has been examined [9].

Biological context of Gzma

• In this report, we have created mice that are deficient for granzyme A and characterized their phenotype [10].
• However, it is unclear to what extent the two main cytolytic pathways, perforin-granzyme A and B exocytosis and Fas ligand (FasL)-Fas interaction, contribute to these processes [11].
• The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells [12].
• We show that rapid CTL-mediated DNA fragmentation of L1210.3 target cells is solely dependent on gzmB, whereas the DNA fragmentation of EL4.F15 target cells by the same CTL population is mainly induced by gzmA and only marginally by gzmB [12].
• Furthermore, granzyme A-deficient mice readily recover from both lymphocytic choriomeningitis virus and Listeria monocytogenes infections and eradicate syngeneic tumors with kinetics similar to the wild-type strain [13].

Anatomical context of Gzma

• Two of them correspond respectively to granzyme A and granzyme B, two proteases expressed by activated T cells [14].
• Residual cytotoxicity and granzyme K expression in granzyme A-deficient cytotoxic lymphocytes [10].
• For both LAK cells and CTL, perforin has been located mostly in the fine granular matrix of the granules, whereas gold particles corresponding to serine esterase have been found in both the matrix and the cap regions of the granules [15].
• Secondly, these transcripts were not found in most of the other cells tested, including in some natural cytotoxic cells and in activated cytotoxic macrophages; however, they could be detected in mast cells for CTLA-1 and in some noncytotoxic lymphocytes for CTLA-3 [16].
• We recently found a novel serine esterase that is present at greatly elevated levels in cloned murine Tc cell lines and one Th/c cell line, but not in two non-cytolytic Th cell lines [17].

Associations of Gzma with chemical compounds

• CTLA-1 and CTLA-3 serine esterase transcripts are detected mostly in cytotoxic T cells, but not only and not always [16].
• A trypsinlike SE activity which cleaves the chromogenic substrate N, alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester was also induced 2- to 4-fold in the presence of the various IL tested [18].
• This nuclear DNA-releasing (NDR) activity is inhibited by serine esterase inhibitors that also inhibit the granule BLT-esterase activity, and is specifically immunoabsorbed by antibodies to the CTL granule protease granzyme A [19].
• A combination of Ac-DEVD-CHO and the granzyme A inhibitor IGA (7-(phenyl-ureido)-4-chloro-3-(2-isothioureidoethoxy)-isocoumarin) inhibited long-term cytolysis [20].
• An expression vector containing antisense cDNA for GA and the gene for hygromycin B resistance was constructed and electroporated into the murine CTL line, AR1 [21].

Physical interactions of Gzma

• It is proposed that granzyme A interacts with the thrombin receptor found on platelets in a manner that is insufficient to cause aggregation, but sufficient to compete with thrombin for the receptor [22].
• In contrast, ligation of the CD3/TCR complex could elicit a rapid cytotoxic response and serine esterase release by IEL [23].
• We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1-specific inhibitory receptor driven by the granzyme A gene [24].

Enzymatic interactions of Gzma

• A synthetic peptide spanning the N-terminal thrombin receptor activation sequence was cleaved by granzyme A at the authentic thrombin cleavage site Leu-Asp-Pro-Arg-Ser [25].

Co-localisations of Gzma

• In PM and IBM, PF positive cells were colocalized with GA positive cells and occasionally invaded into the non-necrotic muscle fibres [3].

Regulatory relationships of Gzma

• We conclude that GzmK expressed by GzmA-deficient T cells accounts for the remaining Z-Lys-SBzl activity [26].
• The spontaneous cytotoxic potential of the DN T cells was further corroborated by demonstrating that the lpr DN T cells constitutively transcribed perforin gene but failed to express granzyme A [27].
• Antibodies to the thrombin receptor inhibited both thrombin and granzyme A-mediated neurite retraction [25].
• Interestingly, production of granzyme A mRNA was strongly induced by 45 min after Con A stimulation [8].
• Both CTLL contain a [3H]DFP-labeled protein that migrates with a molecular mass of 60 kDa under nonreducing conditions and with 30 kDa under reducing conditions and which can be inactivated by the TSP-1-specific inhibitor H-D-Pro-Phe-Arg-chloromethylketone [28].

Other interactions of Gzma

• Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis [29].
• While the self peptide was unable to induce serine esterase release from the CTL, it did induce secretion of IFN-gamma [30].
• CD8 expression positively correlated with perforin and granzyme A, B, and C mRNA, and negatively correlated with IL-4 mRNA levels among these clones [31].
• The Vla1 locus is located 3.5 cM distal to Ctla-3 and 7.8 cM distal to Htrla [32].
• Both mutant receptors were able to prevent apoptosis, but only the mutant that activated STAT1 and STAT3 was able to support induction of granzyme A and L-selectin [33].

Analytical, diagnostic and therapeutic context of Gzma

• The NDR activity comigrates with BLT-esterase activity during subcellular fractionation, solubilization, gel filtration, and aprotinin-Sepharose affinity chromatography [19].
• SDS-PAGE analysis of the affinity-purified product indicates a molecular mass of 60,000 daltons under non-reducing conditions, which moves to 30,000 daltons upon reduction, consistent with previously reported behavior of granzyme A [19].
• Western blot analysis, enzyme assays and reverse transcription-PCR confirmed the absence of granzyme A in activated T cells [13].
• We followed, by in situ hybridization, the appearance of mRNA of the tumor necrosis factor (TNF)-alpha gene and, as a marker for activated cytotoxic T-cells, of the serine protease granzyme A gene in the cellular infiltrates generated by cell transfer at birth [34].
• Cells expressing the genes for granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer [34].

References