Virus Inhibition of RIP3-Dependent Necrosis

• Type of Material: Article
• Authors: Jason W. Upton, Emory University; William Kaiser, Emory University; Edward S Mocarski, Emory University
• Language: English
• Date: 2010-04-22
• Publisher: Elsevier (Cell Press)
• Publication Version: Final Published Version
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chom.2010.03.006
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 7
• Issue: 4
• Start Page: 302
• End Page: 313
• Grant/Funding Information: Supported by N.I.H (PHS grants R01 AI20211 and AI30363 to E.S.M) and (T32 HL069769 and F32 AI080175-01A1 to J.W.U.).
• Keywords: IMMUNE-RESPONSE; Parasitology; INTERACTING PROTEIN RIP; PARASITOLOGY; Life Sciences & Biomedicine; Science & Technology; Virology; VIROLOGY; APOPTOSIS; CELL-DEATH; KINASE RIP; HOMOTYPIC INTERACTION MOTIF; MICROBIOLOGY; MURINE CYTOMEGALOVIRUS; PHOSPHORYLATION; BACULOVIRUS GENE; Microbiology; NF-KAPPA-B
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

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 TNFα-dependent necroptosis. Viral M45-encoded inhibitor of RIP activation (vIRA) targets RIP3 during infection and disrupts RIP3-RIP1 interactions characteristic of TNFα-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. © 2010 Elsevier Inc.