Dissociation of apoptosis and activation of IL-1beta-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG-3.
Recent attention has been focused on the members of the IL-1beta-converting enzyme (ICE)/Ced-3 family of cysteine protease as the key components of programmed cell death. However, the molecular events that lead to protease activation and link it to the final apoptotic processes remain poorly characterized. We have shown recently that ALG-2 is a Ca2+-binding protein required for apoptosis. ALG-2 depletion protects the mouse T cell hybridoma 3DO from programmed cell death induced by several stimuli, such as synthetic glucocorticoids, TCR, and Fas triggering. In this work, we show that in the ALG-2-depleted clones the ICE/Ced-3 proteases are normally activated upon TCR, Fas, and dexamethasone stimulation, as determined by cleavage of the endogenous substrate poly(ADP-ribose) polymerase and of a fluorogenic substrate. ALG-3, a truncated form of the familial Alzheimer's disease gene PS2, confers resistance to TCR- and Fas-induced apoptosis. Of interest, it also reduces protease activity and inhibits poly(ADP-ribose) polymerase cleavage upon Fas triggering. Our results suggest that, during apoptosis, ALG-2 functions downstream of, and that ALG-3 interferes with the sequential activation of members of the ICE family proteases.
Lacanà
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E
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Ganjei
J K
JK
Vito
P
P
D'Adamio
L
L
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics*; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000235:genetics*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D006825:Hybridomas; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D053766:Presenilin-2; D013601:T-Lymphocytes / Q000473:pathology*
D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; C097753:PDCD6 protein, human; C508861:PSEN2 protein, human; C490815:Pdcd6 protein, mouse; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans