Inhibition of proinflammatory and innate immune signaling pathways by a cytomegalovirus RIP1-interacting protein
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.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- February 2008
- DOI:
- 10.1073/pnas.0800168105
- Bibcode:
- 2008PNAS..105.3094M
- Keywords:
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- apoptosis;
- necrosis;
- herpesvirus;
- ribonucleotide reductase;
- Biological Sciences:Microbiology