¹Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, Switzerland

Correspondence: M Thome, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges VD CH-1066, Switzerland. Tel: +41 21 692 57 37; Fax: +41 21 692 57 05; E-mail: Margot.ThomeMiazza@unil.ch

²These two authors contributed equally to this work.

³Current address: Department for Molecular and Experimental Surgery, Clinical Center, University of Erlangen-Nuremberg, Schwabachanlage 10, D-91054 Erlangen, Germany.

Received 22 July 2005; Revised 15 November 2005; Accepted 22 November 2005; Published online 20 January 2006.

Abstract

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.