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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-58098

Geserick, P; Hupe, M; Moulin, M; Wong, W Wei-Lynn; 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):1037-1054.

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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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Deposited On:15 Jun 2012 15:23
Last Modified:13 Aug 2015 09:17
Publisher:Rockefeller University Press
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:10.1083/jcb.200904158
PubMed ID:20038679

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