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PMID: 21737330 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.

Molecular cell ·Vol. 43 ·No. 3 ·2011-08-05 ·Pages 449-63

Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M

Abstract

The intracellular regulation of cell death pathways by cIAPs has been enigmatic. Here we show that loss of cIAPs promotes the spontaneous formation of an intracellular platform that activates either apoptosis or necroptosis. This 2 MDa intracellular complex that we designate "Ripoptosome" is necessary but not sufficient for cell death. It contains RIP1, FADD, caspase-8, caspase-10, and caspase inhibitor cFLIP isoforms. cFLIP(L) prevents Ripoptosome formation, whereas, intriguingly, cFLIP(S) promotes Ripoptosome assembly. When cIAPs are absent, caspase activity is the "rheostat" that is controlled by cFLIP isoforms in the Ripoptosome and decides if cell death occurs by RIP3-dependent necroptosis or caspase-dependent apoptosis. RIP1 is the core component of the complex. As exemplified by our studies for TLR3 activation, our data argue that the Ripoptosome critically influences the outcome of membrane-bound receptor triggering. The differential quality of cell death mediated by the Ripoptosome may cause important pathophysiological consequences during inflammatory responses.

MeSH Terms
Apoptosis/physiology CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism,physiology Caspase 8/metabolism,physiology Cell Line, Tumor Humans Inhibitor of Apoptosis Proteins/physiology Nuclear Pore Complex Proteins/metabolism,physiology Protein Isoforms/physiology RNA-Binding Proteins/metabolism,physiology Receptors, Tumor Necrosis Factor, Type I/metabolism Signal Transduction Toll-Like Receptor 3/metabolism,physiology Tumor Necrosis Factor-alpha/metabolism
Chemicals
AGFG1 protein, human CASP8 and FADD-Like Apoptosis Regulating Protein Inhibitor of Apoptosis Proteins Nuclear Pore Complex Proteins Protein Isoforms RNA-Binding Proteins Receptors, Tumor Necrosis Factor, Type I TLR3 protein, human TNF protein, human Toll-Like Receptor 3 Tumor Necrosis Factor-alpha CASP8 protein, human Caspase 8
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Feoktistova Maria
Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University Heidelberg, Heidelberg, Germany.
Geserick Peter
Kellert Beate
Dimitrova Diana Panayotova
Langlais Claudia
Hupe Mike
Cain Kelvin
MacFarlane Marion
Häcker Georg
Leverkus Martin
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.06.011
Published
2011-08-05
Epub
2011-00-07
Pages
449-63
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3163271
Subset
IM
Grants
Medical Research Council · MC_U132685863 · United Kingdom
Corrections
CommentIn
PMID: 21816342
CommentIn
PMID: 21850033
External Links
PubMed source DOI: 10.1016/j.molcel.2011.06.011 PMC Full Text View journal details
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