Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment
AuthorGeserick, P; Hupe, M; Moulin, M; Wong, WW-L; Feoktistova, M; Kellert, B; Gollnick, H; Silke, J; Leverkus, M
Source TitleThe Journal of Cell Biology
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sSilke, John
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsGeserick, P., Hupe, M., Moulin, M., Wong, W. W. -L., Feoktistova, M., Kellert, B., Gollnick, H., Silke, J. & Leverkus, M. (2009). Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. JOURNAL OF CELL BIOLOGY, 187 (7), pp.1037-1054. https://doi.org/10.1083/jcb.200904158.
Access StatusOpen Access
A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist-induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA-mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIP(L) and not cFLIP(S) interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor-mediated cell death.
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