Virus inhibition of RIP3-dependent necrosis

Jason W. Upton, William J. Kaiser, Edward S. Mocarski

Research output: Contribution to journalArticlepeer-review

371 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)302-313
Number of pages12
JournalCell Host and Microbe
Volume7
Issue number4
DOIs
StatePublished - Apr 22 2010

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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