Virus inhibition of RIP3-dependent necrosis.
Viral infection activates cytokine expression and triggers cell death, the modulation of which is important for successful pathogenesis. Necroptosis is a form of programmed necrosis dependent on two related RIP homotypic interaction motif (RHIM)-containing signaling adaptors, receptor-interacting protein kinases (RIP) 1 and 3. We find that murine cytomegalovirus infection induces RIP3-dependent necrosis. Whereas RIP3 kinase activity and RHIM-dependent interactions control virus-associated necrosis, virus-induced death proceeds independently of RIP1 and is therefore distinct from TNFalpha-dependent necroptosis. Viral M45-encoded inhibitor of RIP activation (vIRA) targets RIP3 during infection and disrupts RIP3-RIP1 interactions characteristic of TNFalpha-induced necroptosis, thereby suppressing both death pathways. Importantly, attenuation of vIRA mutant virus in wild-type mice is normalized in RIP3-deficient mice. Thus, vIRA function validates necrosis as central to host defense against viral infections and highlights the benefit of multiple virus-encoded cell-death suppressors that inhibit not only apoptotic, but also necrotic mechanisms of virus clearance.
Upton
Jason W
JW
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kaiser
William J
WJ
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: wkaiser@emory.edu.
Mocarski
Edward S
ES
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D054884:Host-Pathogen Interactions; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000472:pathogenicity*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D012469:Salivary Glands / Q000821:virology; D013154:Spleen / Q000821:virology; D016019:Survival Analysis; D019562:Viral Load; D014764:Viral Proteins / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
D014764:Viral Proteins; D037521:Virulence Factors; D012264:Ribonucleotide Reductases; C422747:m45 protein, Mouse cytomegalovirus 1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse