Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways

Lisa P. Daley-Bauer, Linda Roback, Lynsey N. Crosby, A. Louise McCormick, Yanjun Feng, William J. Kaiser, Edward S. Mocarski

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase- 8 activates caspase-3 to drive apoptosis with subsequent RIP3- dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by ΔM36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-inhand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.

Original languageEnglish (US)
Pages (from-to)E2786-E2795
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number13
DOIs
StatePublished - Mar 28 2017

Keywords

  • Caspase-8
  • Cell death
  • Inflammation
  • MCMV
  • RIP3 kinase

ASJC Scopus subject areas

  • General

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