title: TWEAK induces apoptosis through a death-signaling complex comprising receptor-interacting protein 1 (RIP1), Fas-associated death domain (FADD), and caspase-8.
abstract: The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TNFSF12, CD255) (TWEAK) can stimulate apoptosis in certain cancer cells. Previous studies suggest that TWEAK activates cell death indirectly, by inducing TNFα-mediated autocrine signals. However, the underlying death-signaling mechanism has not been directly defined. Consistent with earlier work, TWEAK assembled a proximal signaling complex containing its cognate receptor FN14, the adaptor TRAF2, and cellular inhibitor of apoptosis protein 1 (cIAP1). Neither the death domain adaptor Fas-associated death domain nor the apoptosis-initiating protease caspase-8 associated with this primary complex. Rather, TWEAK induced TNFα secretion and TNF receptor 1-dependent assembly of a death-signaling complex containing receptor-interacting protein 1 (RIP1), FADD, and caspase-8. Knockdown of RIP1 by siRNA prevented TWEAK-induced association of FADD with caspase-8 but not formation of the FN14-TRAF2-cIAP1 complex and inhibited apoptosis activation. Depletion of the RIP1 E3 ubiquitin ligase cIAP1 enhanced assembly of the RIP1-FADD-caspase-8 complex and augmented cell death. Conversely, knockdown of the RIP1 deubiquitinase CYLD inhibited these functions. Depletion of FADD, caspase-8, BID, or BAX and BAK but not RIP3 attenuated TWEAK-induced cell death. Pharmacologic inhibition of the NF-κB pathway or siRNA knockdown of RelA attenuated TWEAK induction of TNFα and association of RIP1 with FADD and caspase-8. These results suggest that TWEAK triggers apoptosis by promoting assembly of a RIP1-FADD-caspse-8 complex via autocrine TNFα-TNFR1 signaling. The proapoptotic activity of TWEAK is modulated by cIAP1 and CYLD and engages both the extrinsic and intrinsic signaling pathways.
authors.affiliation: Department of Molecular Oncology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Aminah
authors.initials: A
authors.lastname: Ikner
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D000074049:Cytokine TWEAK; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
chemical_list: C119724:AGFG1 protein, human; D000074049:Cytokine TWEAK; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; D025801:Ubiquitin; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8