Target cell lysis by CTL granule exocytosis is independent of ICE/Ced-3 family proteases.
Activation of ICE/Ced-3 family proteases (caspases) has been proposed to mediate both the granule exocytosis and Fas-Fas ligand pathways of rapid target cell death by cytotoxic T lymphocytes. In agreement with this model, two peptide fluoromethyl ketone caspase inhibitors and baculovirus p35 blocked apoptotic nuclear damage and target cell lysis by the CTL-mediated Fas-Fas ligand pathway. The peptide caspase inhibitors also blocked drug-induced apoptotic cell death in tumor cells. In contrast, the caspase inhibitors blocked CTL granule exocytosis-induced target apoptotic nuclear damage, but did not inhibit target lysis. These results are consistent with recent demonstrations that granzyme B can activate caspases leading to apoptotic nuclear damage, but show that target cell lysis by CTL granule exocytosis occurs by a caspase-independent pathway.
Sarin
A
A
Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Williams
M S
MS
Alexander-Miller
M A
MA
Berzofsky
J A
JA
Zacharchuk
C M
CM
Henkart
P A
PA
D000818:Animals; D029742:Caenorhabditis elegans Proteins; D020170:Caspase 1; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000032:analysis*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology*; D015801:Helminth Proteins / Q000032:analysis*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans; D020170:Caspase 1