Molecular Cell
Volume 43, Issue 3, 5 August 2011, Pages 432-448
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Article
The Ripoptosome, a Signaling Platform that Assembles in Response to Genotoxic Stress and Loss of IAPs

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Summary

A better understanding of the mechanisms through which anticancer drugs exert their effects is essential to improve combination therapies. While studying how genotoxic stress kills cancer cells, we discovered a large ∼2MDa cell death-inducing platform, referred to as “Ripoptosome.” It contains the core components RIP1, FADD, and caspase-8, and assembles in response to genotoxic stress-induced depletion of XIAP, cIAP1 and cIAP2. Importantly, it forms independently of TNF, CD95L/FASL, TRAIL, death-receptors, and mitochondrial pathways. It also forms upon Smac-mimetic (SM) treatment without involvement of autocrine TNF. Ripoptosome assembly requires RIP1's kinase activity and can stimulate caspase-8-mediated apoptosis as well as caspase-independent necrosis. It is negatively regulated by FLIP, cIAP1, cIAP2, and XIAP. Mechanistically, IAPs target components of this complex for ubiquitylation and inactivation. Moreover, we find that etoposide-stimulated Ripoptosome formation converts proinflammatory cytokines into prodeath signals. Together, our observations shed new light on fundamental mechanisms by which chemotherapeutics may kill cancer cells.

Highlights

► Genotoxic stress and depletion of IAPs triggers the formation of the Ripoptosome ► The Ripoptosome can stimulate apoptosis as well as necrosis in cancer cells ► It can form independently of mitochondrial and death-receptor pathways ► cFLIP and IAPs negatively regulate Ripoptosome-mediated apoptosis and necrosis

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These authors contributed equally to this work

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Present address: Section of Cancer Genetics, Sir Richard Doll Building, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK