cIAP1 and TAK1 Protect Cells from TNF-induced Necrosis by Preventing RIP1/RIP3-Dependent Reactive Oxygen Species Production

Peter Vandenabeele (1) , Nele Vanlangenakker (1) , Tom Vanden Berghe (1) , Pieter Bogaert (1) , Bram Laukens (1) , Kerry Zobel (1) , Kurt Deshayes (1) , Vucic Domagoj (1) , Simone Fulda (1) , Mathieu J.M. Bertrand (1)

1 Department for Molecular Biomedical Research

Three members of the IAP family (XIAP, cIAP1 and cIAP2) are potent suppressors of apoptosis. Recent studies have shown that cIAP1 and cIAP2, unlike XIAP, are not direct caspase inhibitors but block apoptosis by functioning as E3 ligases for effector caspases and RIP1. cIAP-mediated polyubiquitination of RIP1 allows it to bind to the pro-survival kinase TAK1 that prevents it from activating caspase-8 dependent death, a process reverted by the de-ubiquitinase CYLD. RIP1 is also a regulator of necrosis, a caspase-independent type of cell death. Here, we show that cells depleted of the IAPs by treatment with the IAP antagonist BV6 are greatly sensitized to TNF-induced necrosis but not to necrotic death induced by anti-Fas, poly(I:C) or by oxidative stress. Specific targeting of the IAPs by RNAi revealed that repression of cIAP1 is responsible for the sensitization. Similarly, lowering TAK1 levels or inhibiting its kinase activity sensitized cells to TNF-induced necrosis whereas repressing CYLD had opposite effects. We show that this sensitization to death is accompanied by enhanced RIP1 kinase activity, increased recruitment of RIP1 to FADD and RIP3 allowing necrosome formation, and elevated RIP1 kinase-dependent accumulation of reactive oxygen species (ROS). In conclusion, our data indicate that cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent ROS production.

Mots clés: necrosis; smac mimetic; TAK1; cIAP1; necrosome

Peter Vandenabeele, Nele Vanlangenakker, Tom Vanden Berghe, Pieter Bogaert, Bram Laukens, et al.. cIAP1 and TAK1 Protect Cells from TNF-induced Necrosis by Preventing RIP1/RIP3-Dependent Reactive Oxygen Species Production. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.138⟩. ⟨hal-00590748⟩