Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein

doi:10.1073/pnas.0800168105

Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein

*Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany;
^†Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany; and
^‡Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy

Communicated by Thomas E. Shenk, Princeton University, Princeton, NJ, January 7, 2008 (received for review December 10, 2007)

Abstract

TNFα is an important cytokine in antimicrobial immunity and inflammation. The receptor-interacting protein RIP1 is an essential component of the TNF receptor 1 signaling pathway that mediates the activation of NF-κB, MAPKs, and programmed cell death. It also transduces signals derived from Toll-like receptors and intracellular sensors of DNA damage and double-stranded RNA. Here, we show that the murine CMV M45 protein binds to RIP1 and inhibits TNFα-induced activation of NF-κB, p38 MAPK, and caspase-independent cell death. M45 also inhibited NF-κB activation upon stimulation of Toll-like receptor 3 and ubiquitination of RIP1, which is required for NF-κB activation. Hence, M45 functions as a viral inhibitor of RIP1-mediated signaling. The results presented here reveal a mechanism of viral immune subversion and demonstrate how a viral protein can simultaneously block proinflammatory and innate immune signaling pathways by interacting with a central mediator molecule.

Footnotes

^§To whom correspondence should be addressed. E-mail: BruneW{at}rki.de
Author contributions: C.M. and W.B. designed research; C.M. and A.S. performed research; D.L. contributed new reagents/analytic tools; C.M., A.S., and W.B. analyzed data; and C.M., D.L., and W.B. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0800168105/DC1.