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.
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Abbreviations
- CTL:
-
cytotoxic T lymphocyte
- DD:
-
death domain
- DED:
-
death effector domain
- DISC:
-
death-inducing signaling complex
- FLIP:
-
Flice/caspase-8 inhibitory protein
- MCV:
-
molluscum contagiosum virus
- TNF:
-
tumor necrosis factor
- TRAF:
-
TNF receptor-associated factor
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Acknowledgements
We thank Daniel Legler, Fabio Martinon, Olivier Micheau and Pascal Schneider for discussions and comments on the manuscript. This work was supported by grants of the Swiss Cancer League and the Swiss National Science Foundation to M Thome and J Tschopp, by a research fellowship of the Deutsche Forschungsgesellschaft to M Thurau, and by an EMBO long-term fellowship to H Everett.
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Thurau, M., Everett, H., Tapernoux, M. et al. The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis. Cell Death Differ 13, 1577–1585 (2006). https://doi.org/10.1038/sj.cdd.4401847
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DOI: https://doi.org/10.1038/sj.cdd.4401847
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