The cytotoxic T cell proteinase granzyme B does not activate interleukin-1 beta-converting enzyme.

Darmon, Alison J.; Ehrman, N; Caputo, Annalisa; Fujinaga, Jocelyne; Bleackley, R. Chris

doi:10.1016/s0021-9258(18)31596-5

Cited by 52 publications

(1 citation statement)

References 25 publications

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“…Caspases 8 and 10 are upstream caspases that bear the preferred GraB IEXD motif at the interchain processing site (4,13) and have been shown to be processed during GraB and CTL apoptosis (20,45), although caspase 10 is more readily processed by GraB in vitro than are other caspases (20). Although some cells derived from mice deficient in caspase 1 are more resistant to GraB (46), caspase 1 cannot be processed by GraB directly in vitro (47). Thus, a YVAD-inhibitable caspase 1-like protease may participate in the pathway but is probably not the primary target for GraB.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis

MacDonald

Shi

Velde

et al. 1999

The Journal of Experimental Medicine

170

124

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Granzyme B (GraB) is required for the efficient activation of apoptosis by cytotoxic T lymphocytes and natural killer cells. We find that GraB and perforin induce severe mitochondrial perturbation as evidenced by the release of cytochrome c into the cytosol and suppression of transmembrane potential (Δψ). The earliest mitochondrial event was the release of cytochrome c, which occurred at the same time as caspase 3 processing and consistently before the activation of apoptosis. Granzyme K/perforin or perforin treatment, both of which kill target cells efficiently but are poor activators of apoptosis in short-term assays, did not induce rapid cytochrome c release. However, they suppressed Δψ and increased reactive oxygen species generation, indicating that mitochondrial dysfunction is also associated with this nonapoptotic cell death.Pretreatment with peptide caspase inhibitors zVAD-FMK or YVAD-CHO prevented GraB apoptosis and cytochrome c release, whereas DEVD-CHO blocked apoptosis but did not prevent cytochrome c release, indicating that caspases act both up- and downstream of mitochondria. Of additional interest, Δψ suppression mediated by GraK or GraB and perforin was not affected by zVAD-FMK and thus was caspase independent. Overexpression of Bcl-2 and Bcl-XL suppressed caspase activation, mitochondrial cytochrome c release, Δψ suppression, and apoptosis and cell death induced by GraB, GraK, or perforin.In an in vitro cell free system, GraB activates nuclear apoptosis in S-100 cytosol at high doses, however the addition of mitochondria amplified GraB activity over 15-fold. GraB- induced caspase 3 processing to p17 in S-100 cytosol was increased only threefold in the presence of mitochondria, suggesting that another caspase(s) participates in the mitochondrial amplification of GraB apoptosis. We conclude that GraB-induced apoptosis is highly amplified by mitochondria in a caspase-dependent manner but that GraB can also initiate caspase 3 processing and apoptosis in the absence of mitochondria.

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Section: Discussionmentioning

confidence: 99%

Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis

MacDonald

Shi

Velde

et al. 1999

The Journal of Experimental Medicine

170

124

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CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Thomas

Hersey

1998

Int. J. Cancer

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Previous studies have shown that CD4 T cells are associated with regression in primary melanoma and rejection of tumors in adoptive transfer models. The mechanism by which they mediate their anti‐tumor effects remains unclear, and some studies have suggested that Fas ligand (FasL)/Fas interactions were involved. In the present study, we have examined the cytotoxic mechanism involved in CD4 T‐cell killing of melanoma cells and, in particular, the role of FasL/Fas interactions in this killing. We show that the CD4 T cells in 4 clones of T cells induced apoptosis in autologous melanoma cells by MHC‐restricted mechanisms but lysed an allogeneic melanoma cell by a non‐apoptotic mechanism. Melanoma cells expressed both Fas and FasL, but killing of melanoma cells did not involve Fas/FasL interactions. This was shown by a lack of correlation between Fas expression and susceptibility to lysis and by failure of a monoclonal antibody to Fas to block killing by the CD4 T cells, though the latter expressed FasL. Recombinant FasL did not induce killing of melanoma cells. Int. J. Cancer 75:384–390, 1998. © 1998 Wiley‐Liss, Inc.

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Cleavage of caspase family members by granzyme B: a comparative study in vitro

et al. 1997

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The aspartase granzyme B is one of the major components of the granules involved in cell killing by cytotoxic T lymphocytes. Granzyme B has been shown to activate the apoptotic death pathway in the target cell, and this involves activation of members of the caspase (CASP) protein family. Therefore, activational cleavage of mouse (m) CASP proforms by granzyme B was examined in vitro. CASP can be subdivided in the CASP-1 (interleukin-1 beta-converting enzyme; ICE) subfamily, the CASP-2 (Ich1) subfamily, and the CASP-3 (CPP32) subfamily. Our results reveal that the proforms of the CASP-3 subfamily members mCASP-3 and mCASP-7 are hydrolyzed by granzyme B, while proforms of CASP-2 and CASP-1 subfamily members are not directly cleaved. Only one CASP-3 subfamily member, pro-mCASP-6, was not proteolytically cleaved by granzyme B. These results indicate that two members of the CASP-3 subfamily, but no others, become activated by granzyme B.

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The cytotoxic T cell proteinase granzyme B does not activate interleukin-1 beta-converting enzyme.

Cited by 52 publications

References 25 publications

Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis

Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Cleavage of caspase family members by granzyme B: a comparative study in vitro

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