title: dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8.
abstract: Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-α (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2-TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas- or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, UMR5286 CNRS/INSERM/Université Lyon 1 UCBL, Lyon, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Estornes
authors.forename: F
authors.initials: F
authors.lastname: Toscano
authors.forename: F
authors.initials: F
authors.lastname: Virard
authors.forename: G
authors.initials: G
authors.lastname: Jacquemin
authors.forename: A
authors.initials: A
authors.lastname: Pierrot
authors.forename: B
authors.initials: B
authors.lastname: Vanbervliet
authors.forename: M
authors.initials: M
authors.lastname: Bonnin
authors.forename: N
authors.initials: N
authors.lastname: Lalaoui
authors.forename: P
authors.initials: P
authors.lastname: Mercier-Gouy
authors.forename: Y
authors.initials: Y
authors.lastname: Pachéco
authors.forename: B
authors.initials: B
authors.lastname: Salaun
authors.forename: T
authors.initials: T
authors.lastname: Renno
authors.forename: O
authors.initials: O
authors.lastname: Micheau
authors.forename: S
authors.initials: S
authors.lastname: Lebecque
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
chemical_list: C119724:AGFG1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D028861:Nuclear Pore Complex Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; C495344:TLR3 protein, human; D053199:TNF Receptor-Associated Death Domain Protein; D047992:TNF Receptor-Associated Factor 2; D051196:Toll-Like Receptor 3; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C505530:CASP8 protein, human; D053181:Caspase 8