[PDF][PDF] The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs

T Tenev, K Bianchi, M Darding, M Broemer, C Langlais… - Molecular cell, 2011 - cell.com
T Tenev, K Bianchi, M Darding, M Broemer, C Langlais, F Wallberg, A Zachariou, J Lopez…
Molecular cell, 2011cell.com
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 …
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.
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