Alternative titles; symbols
HGNC Approved Gene Symbol: GZMB
Cytogenetic location: 14q12 Genomic coordinates (GRCh38): 14:24,630,954-24,634,190 (from NCBI)
In a differential cDNA bank, Brunet et al. (1986) detected 3 distinct mRNA transcripts (CTLA1, CTLA2, and CTLA3) in various cytotoxic T-cells but not (or less so) in a range of noncytotoxic lymphoid cells. They described the coinducibility of these transcripts, the sequence of CTLA1 cDNA, and its protein homology with serine esterases.
Klein et al. (1989) isolated and sequenced the cytotoxic serine protease B gene. Due to faulty or at least variable intron/exon splicing, the mRNA transcripts from the human serine protease gene are heterogeneous in size. Two cryptic splice sites, used to generate these aberrant mRNA transcripts, were identified.
Hanson et al. (1990) used a cathepsin G cDNA probe (see 116830) to clone 2 cathepsin G-like genes (designated CGL1 and CGL2) from a human genomic library. They determined that CGL1 is identical to the previously identified gene CTLA1, or serine protease B, that is expressed only in activated cytotoxic T lymphocytes.
Dahl et al. (1990) isolated cDNA clones from a human NK cell cDNA library that encode granzyme B. They suggested that the granzyme B gene is homologous to that for CTLA1.
Rissoan et al. (2002) detected granzyme B mRNA in both resting and activated plasmacytoid dendritic cells and at much lower levels in monocytes, resting T cells, B cells, activated granulocytes, and activated monocyte-derived dendritic cells. It was barely detectable in nonactivated monocyte-derived dendritic cells.
The serine proteinase GZMB is crucial for the rapid induction of target cell apoptosis by cytotoxic T cells. GZMB enters cells in a perforin-independent manner, predicting the existence of a cell surface receptor(s). Motyka et al. (2000) presented evidence that this receptor is the cation-independent mannose 6-phosphate receptor (CIMPR), also called IGF2R (147280). Inhibition of the GZMB-IGF2R interaction prevented GZMB cell surface binding, uptake, and the induction of apoptosis. Significantly, expression of IGF2R was essential for cytotoxic T cell-mediated apoptosis of target cells in vitro and for the rejection of allogeneic cells in vivo.
Winrow et al. (2005) studied T-cell lymphomas isolated from mice with mutations in Atm (607585) and/or p53 (191170) using cytogenetic analysis and mRNA transcriptional profiling. They identified a recurrent disruption of the granzyme gene family locus resulting in an aberrant Gzmb/Gzmc fusion product.
Huang et al. (2006) found that NFKB (see 164011)-specific inhibitors suppressed GZMB mRNA and protein expression in an IL2 (147680)-dependent NK cell line and in primary human NK cells. Bioinformatic, ChIP, and EMSA analyses identified a functional NFKB-binding site (GGAGATTCCC) downstream of GZMB that controlled GZMB expression in NK cells, as well as in Jurkat T cells.
Klein et al. (1989) found that the cytotoxic serine protease B gene is approximately 3,500 bp long, consisting of 5 exons and 4 introns.
Haddad et al. (1990) reported that the CTLA1 gene is about 4.75 kb long.
Brunet et al. (1986) found by in situ hybridization that the Ctla1 gene maps to the D segment of mouse chromosome 14, where the Tcra gene (see 186880) is also situated. Preliminary experiments suggested that the human gene might also be situated close to TCRA. Such was confirmed by Harper et al. (1988). In addition to in situ hybridization, linkage analysis was performed using interspecific mouse backcrosses; no recombination was observed in 100 backcross products studied.
Using DNA blot analysis on a panel of human-rodent somatic cell lines, Klein et al. (1989) localized the CSPB gene to chromosome 14.
Using a human cell line with an inversion on chromosome 14, Harper et al. (1988) showed that the order of loci on 14q is NP (164050)--TCRA--CTLA1. Two components of the complement cascade that possess serine protease domains, namely, C2 and factor B, map close to the MHC class I and class II loci. The serine esterase trypsin gene maps close to the TCRB locus. The close proximity of TCRA and CTLA1 provides another example of the proximity of genes coding for a member of the Ig superfamily and a serine esterase.
Hanson et al. (1990) showed that cathepsin G (116830), CGL1, and CGL2 (116831) are linked on a 50-kb segment in band 14q11.2. Thus, this gene cluster maps to the same chromosomal band as the alpha and delta T-cell receptor gene--a region involved in most chromosomal translocations and inversions specifically associated with T-cell malignancies. For the physical linkage studies of the 3 genes, Hanson et al. (1990) screened a human cosmid library with probes for all 3 genes. In this way they found that CGL1 and CGL2 are separated by about 21 kb, and that the cathepsin G gene is about 31 kb downstream of CGL2. The 3 genes are in the same 5-prime to 3-prime orientation. The murine homolog of CGL1 has been mapped to mouse chromosome 14 (Crosby et al., 1990). Band 14q11.2 contains a cluster of genes involved in hematopoietic development: CGL1 in activated cytotoxic lymphocytes, cathepsin G in promyelocytes and promonocytes and the alpha/delta T-cell receptor genes in early T-cell ontogeny. Lin et al. (1990) also assigned CTLA1, as well as another serine protease gene, to 14q11.2-q12 by in situ hybridization.
By Southern analysis of rodent-human hybrid cells retaining various chromosome 14 rearrangements, Dahl et al. (1990) localized the gene to 14q11-q32, distal to the T cell receptor alpha locus and proximal to the immunoglobulin heavy chain locus.
Knickelbein et al. (2008) found that mice lacking Prf1 (170280) or Gzmb cleared herpes simplex virus (HSV) type-1 as well as wildtype mice, but that latency was unstable in their trigeminal ganglia (TG). Neuronal latency in vivo and in TG cultures depended on the presence of lytic granules from Cd8 (seea186910)-positive T cells, in addition to Ifng (147570) produced by these cells, which surround the TG. Viral inactivation could be mediated by Gzmb, which degraded the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression. Knickelbein et al. (2008) concluded that CD8-positive T-cell lytic granules can block the HSV-1 life cycle and viral replication and reactivation through a nonlytic mechanism with direct cleavage of ICP4 by GZMB.
Bannard et al. (2009) generated transgenic mice expressing Gzmb in Cd8-positive T cells conditionally and indelibly marked with enhanced yellow fluorescent (EYFP) protein. They found that virus-specific Cd8-positive T cells expressed Gzmb within the first 2 days of a primary response to influenza infection and continued primary clonal expansion. On secondary infection, both EYFP-positive Cd8-positive T cells from primary infection and all virus-specific Cd8-positive T cells clonally expanded. Bannard et al. (2009) concluded that CD8-positive T cells with effector phenotype during primary infection may function as memory cells with replicative function.
Bannard, O., Kraman, M., Fearon, D. T. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 323: 505-509, 2009. [PubMed: 19164749] [Full Text: https://doi.org/10.1126/science.1166831]
Brunet, J.-F., Dosseto, M., Denizot, F., Mattei, M.-G., Clark, W. R., Haqqi, T. M., Ferrier, P., Nabholz, M., Schmitt-Verhulst, A.-M., Luciani, M.-F., Golstein, P. The inducible cytotoxic T-lymphocyte-associated gene transcript CTLA-1 sequence and gene localization to mouse chromosome 14. Nature 322: 268-271, 1986. [PubMed: 3090449] [Full Text: https://doi.org/10.1038/322268a0]
Crosby, J. L., Bleackley, R. C., Nadeau, J. H. A complex of serine protease genes expressed preferentially in cytotoxic T-lymphocytes is closely linked to the T-cell receptor alpha- and delta-chain genes on mouse chromosome 14. Genomics 6: 252-259, 1990. [PubMed: 2307468] [Full Text: https://doi.org/10.1016/0888-7543(90)90564-b]
Dahl, C. A., Bach, F. H., Chan, W., Huebner, K., Russo, G., Croce, C. M., Herfurth, T., Cairns, J. S. Isolation of a cDNA clone encoding a novel form of granzyme B from human NK cells and mapping to chromosome 14. Hum. Genet. 84: 465-470, 1990. [PubMed: 2323780] [Full Text: https://doi.org/10.1007/BF00195821]
Haddad, P., Clement, M.-V., Bernard, O., Larsen, C.-J., Degos, L., Sasportes, M., Mathieu-Mahul, D. Structural organization of the CTLA-1 gene encoding human granzyme B. Gene 87: 265-271, 1990. [PubMed: 2332171] [Full Text: https://doi.org/10.1016/0378-1119(90)90311-e]
Hanson, R. D., Hohn, P. A., Popescu, N. C., Ley, T. J. A cluster of hematopoietic serine protease genes is found on the same chromosomal band as the human alpha/delta T-cell receptor locus. Proc. Nat. Acad. Sci. 87: 960-963, 1990. [PubMed: 2300587] [Full Text: https://doi.org/10.1073/pnas.87.3.960]
Harper, K., Mattei, M.-G., Simon, D., Suzan, M., Guenet, J.-L., Haddad, P., Sasportes, M., Golstein, P. Proximity of the CTLA-1 serine esterase and Tcr(alpha) loci in mouse and man. Immunogenetics 28: 439-444, 1988. [PubMed: 3182016] [Full Text: https://doi.org/10.1007/BF00355376]
Huang, C., Bi, E., Hu. Y., Deng, W., Tian, Z., Dong, C., Hu, Y., Sun, B. A novel NF-kappa-B binding site controls human granzyme B gene transcription. J. Immun. 176: 4173-4181, 2006. [PubMed: 16547254] [Full Text: https://doi.org/10.4049/jimmunol.176.7.4173]
Klein, J. L., Shows, T. B., Dupont, B., Trapani, J. A. Genomic organization and chromosomal assignment for a serine protease gene (CSP-B), expressed by human cytotoxic lymphocytes. Genomics 5: 110-117, 1989. [PubMed: 2788607] [Full Text: https://doi.org/10.1016/0888-7543(89)90093-1]
Knickelbein, J. E., Khanna, K. M., Yee, M. B., Baty, C. J., Kinchington, P. R., Hendricks, R. L. Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322: 268-271, 2008. [PubMed: 18845757] [Full Text: https://doi.org/10.1126/science.1164164]
Lin, C. C., Meier, M., Sorensen, O., Sasi, R., Tainaka, T., Bleackley, R. C. Chromosome localization of two human serine protease genes to region 14q11.2-q12 by in situ hybridization. Cytogenet. Cell Genet. 53: 169-171, 1990. [PubMed: 2369846] [Full Text: https://doi.org/10.1159/000132921]
Motyka, B., Korbutt, G., Pinkoski, M. J., Heibein, J. A., Caputo, A., Hobman, M., Barry, M., Shostak, I., Sawchuk, T., Holmes, C. F. B., Gauldie, J., Bleackley, R. C. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103: 491-500, 2000. [PubMed: 11081635] [Full Text: https://doi.org/10.1016/s0092-8674(00)00140-9]
Rissoan, M.-C., Duhen, T., Bridon, J.-M., Bendriss-Vermare, N., Peronne, C., Saint Vis, B., Briere, F., Bates, E. E. M. Subtractive hybridization reveals the expression of immunoglobulinlike transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells. Blood 100: 3295-3303, 2002. [PubMed: 12384430] [Full Text: https://doi.org/10.1182/blood-2002-02-0638]
Winrow, C. J., Pankratz, D. G., Vibat, C. R. T., Bowen, T. J., Callahan, M. A., Warren, A. J., Hilbush, B. S., Wynshaw-Boris, A., Hasel, K. W., Weaver, Z., Lockhart, D. J., Barlow, C. Aberrant recombination involving the granzyme locus occurs in Atm-/- T-cell lymphomas. Hum. Molec. Genet. 14: 2671-2684, 2005. [PubMed: 16087685] [Full Text: https://doi.org/10.1093/hmg/ddi301]