The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways

Nat Immunol. 2007 Jun;8(6):592-600. doi: 10.1038/ni1465. Epub 2007 Apr 29.

Abstract

Intracellular detection of RNA virus infection is mediated by the RNA helicase RIG-I, which is recruited to mitochondria by the adaptor protein MAVS and triggers activation of the transcription factors NF-kappaB, IRF3 and IRF7. Here we demonstrate that virus-induced activation of IRF3 and IRF7 depended on the NF-kappaB modulator NEMO, which acted 'upstream' of the kinases TBK1 and IKKepsilon. IRF3 phosphorylation, formation of IRF3 dimers and DNA binding, as well as IRF3-dependent gene expression, were abrogated in NEMO-deficient cells. IRF3 phosphorylation and interferon production were restored by ectopic expression of NEMO. Thus, NEMO, like MAVS, acts as an adaptor protein that allows RIG-I to activate both the NF-kappaB and IRF signaling pathways.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Interferon Regulatory Factors / metabolism*
  • Interferons / biosynthesis
  • Interferons / genetics
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Viruses / physiology
  • Signal Transduction*
  • Virus Replication

Substances

  • Adaptor Proteins, Signal Transducing
  • IKBKG protein, human
  • Interferon Regulatory Factors
  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • NF-kappa B
  • TANK protein, human
  • Interferons
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases