[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, 2011•cell.comA 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 …
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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