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- Title
Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment.
- Authors
Geserick, Peter; Hupe, Mike; Moulin, Maryline; Wong, W. Wei-Lynn; Feoktistova, Maria; Kellert, Beate; Gollnick, Harald; Silke, John; Leverkus, Martin
- Abstract
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[sub L] and not cFLIP[sub 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.
- Subjects
CELL death; CD antigens; PROTEIN kinases; APOPTOSIS; LIGANDS (Biochemistry); CYTOPLASM
- Publication
Journal of Cell Biology, 2009, Vol 187, Issue 7, p1037
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200904158