Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein.
TNFalpha 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-kappaB, 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 TNFalpha-induced activation of NF-kappaB, p38 MAPK, and caspase-independent cell death. M45 also inhibited NF-kappaB activation upon stimulation of Toll-like receptor 3 and ubiquitination of RIP1, which is required for NF-kappaB 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.
Mack
Claudia
C
Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany.
Sickmann
Albert
A
Lembo
David
D
Brune
Wolfram
W
D000818:Animals; D015153:Blotting, Western; D020690:GTPase-Activating Proteins / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D047468:Immunoprecipitation; D008156:Luciferases; D051379:Mice; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014764:Viral Proteins / Q000276:immunology* / Q000494:pharmacology
D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D008156:Luciferases; D012264:Ribonucleotide Reductases; C422747:m45 protein, Mouse cytomegalovirus 1