Virus inhibition of RIP3-dependent necrosis

Cell Host Microbe. 2010 Apr 22;7(4):302-313. doi: 10.1016/j.chom.2010.03.006.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Death*
  • Cell Line
  • Cell Survival
  • Host-Pathogen Interactions*
  • Humans
  • Liver / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muromegalovirus / pathogenicity*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Ribonucleotide Reductases / metabolism*
  • Salivary Glands / virology
  • Spleen / virology
  • Survival Analysis
  • Viral Load
  • Viral Proteins / metabolism*
  • Virulence
  • Virulence Factors / metabolism*


  • Viral Proteins
  • Virulence Factors
  • Ribonucleotide Reductases
  • m45 protein, Mouse cytomegalovirus 1
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse