The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis.
Members of the viral Flice/caspase-8 inhibitory protein (v-FLIP) family prevent induction of apoptosis by death receptors through inhibition of the processing and activation of procaspase-8 and -10 at the level of the receptor-associated death-inducing signaling complex (DISC). Here, we have addressed the molecular function of the v-FLIP member MC159 of the human molluscum contagiosum virus. MC159 FLIP powerfully inhibited both caspase-dependent and caspase-independent cell death induced by Fas. The C-terminal region of MC159 bound TNF receptor-associated factor (TRAF)3, was necessary for optimal TRAF2 binding, and mediated the recruitment of both TRAFs into the Fas DISC. TRAF-binding-deficient mutants of MC159 showed impaired inhibition of FasL-induced caspase-8 processing and Fas internalization, and had reduced antiapoptotic activity. Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death.
Thurau
M
M
Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, Switzerland.
Everett
H
H
Tapernoux
M
M
Tschopp
J
J
Thome
M
M
D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053455:Caspase 10 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D053222:Fas Ligand Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D018169:Molluscipoxvirus / Q000378:metabolism*; D009336:Necrosis; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014764:Viral Proteins; D053455:Caspase 10; D053181:Caspase 8