Cell Host & Microbe
Volume 7, Issue 4, 22 April 2010, Pages 302-313
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Article
Virus Inhibition of RIP3-Dependent Necrosis

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Summary

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.

Highlights

► Murine cytomegalovirus infection (MCMV) activates RIP3-dependent necrosis ► RIP3 kinase activity and RHIM-dependent interactions control virus-associated necrosis ► Viral M45-encoded inhibitor of RIP activation targets RIP3 to suppress necrosis ► The MCMV M45 mutant phenotype is normalized in RIP3-deficient mice

MICROBIO
CELLBIO
SIGNALING

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2

These authors contributed equally to this work