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). cIAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. Journal of Cell Biology, 187(7):1037-1054.
|Published Version (English)|
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 cFLIPL and not cFLIPS 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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|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:||03 Dec 2012 20:49|
|Publisher:||Rockefeller University Press|
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