title: The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.
abstract: 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.
authors: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK. tencho.tenev@icr.ac.uk
authors: Tencho
authors: T
authors: Tenev
authors: Katiuscia
authors: K
authors: Bianchi
authors: Maurice
authors: M
authors: Darding
authors: Meike
authors: M
authors: Broemer
authors: Claudia
authors: C
authors: Langlais
authors: Fredrik
authors: F
authors: Wallberg
authors: Anna
authors: A
authors: Zachariou
authors: Juanita
authors: J
authors: Lopez
authors: Marion
authors: M
authors: MacFarlane
authors: Kelvin
authors: K
authors: Cain
authors: Pascal
authors: P
authors: Meier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053181:Caspase 8 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000502:physiology; D008024:Ligands; D008928:Mitochondria / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C119724:AGFG1 protein, human; D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D005047:Etoposide; C505530:CASP8 protein, human; D053181:Caspase 8