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

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journal contribution
posted on 11.04.2016, 08:30 by M. Feoktistova, P. Geserick, B. Kellert, D. P. Dimitrova, Claudia Langlais, M. Hupe, K. Cain, Marion MacFarlane, G. Häcker, M. Leverkus
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.

History

Citation

Molecular Cell, 2011, 43 (3), pp. 449-463

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Molecular Cell

Publisher

Elsevier (Cell Press)

issn

1097-2765

eissn

1097-4164

Acceptance date

17/06/2001

Copyright date

2011

Available date

11/04/2016

Publisher version

http://www.sciencedirect.com/science/article/pii/S1097276511004527

Language

en