Journal
JOURNAL OF CELL BIOLOGY
Volume 187, Issue 7, Pages 1037-1054Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200904158
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Funding
- Association pour la Recherche sur le Cancer
- National Health and Medical Research Council [433013, 356256, 461221, 541901, 541902]
- Wilhelm-Sander-Stiftung [2008.072.1]
- Deutsche Krebshilfe [106849]
- Deutsche Forschungsgemeinschaft [Le 953/5-1]
- Graduiertenkolleg [1167, TP6.1]
- Exzellenzfrderung [N2/C2, TP6]
- Berliner Stiftung fur Dermatologie
- TetraLogic Corp
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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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