Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection

Nat Immunol. 2013 May;14(5):480-8. doi: 10.1038/ni.2563. Epub 2013 Mar 24.

Abstract

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.

Publication types

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

MeSH terms

  • Animals
  • Autophagy-Related Protein-1 Homolog
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Immunity, Active / genetics
  • Inflammasomes / metabolism*
  • Influenzavirus A / immunology*
  • Interleukin-18 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / physiology*
  • Mitophagy*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Orthomyxoviridae Infections / immunology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism*
  • Signal Transduction / genetics
  • Superoxides / metabolism
  • Virulence Factors / genetics

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Virulence Factors
  • Superoxides
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Ulk1 protein, mouse
  • Caspase 1