Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Nature. 2005 Oct 20;437(7062):1167-72. doi: 10.1038/nature04193. Epub 2005 Sep 21.

Abstract

Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKalpha, IKKbeta and IKKvarepsilon kinases by means of its C-terminal region, leading to the activation of NF-kappaB and IRF3. Overexpression of Cardif results in interferon-beta and NF-kappaB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Antiviral Agents / immunology
  • Antiviral Agents / metabolism*
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Hepacivirus / enzymology
  • Hepacivirus / immunology
  • Hepacivirus / metabolism*
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factor-3
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Mice
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Helicases / immunology
  • RNA Helicases / metabolism*
  • Substrate Specificity
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Viral Nonstructural Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • NF-kappa B
  • NS3 protein, hepatitis C virus
  • Transcription Factors
  • VISA protein, human
  • Viral Nonstructural Proteins
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • RNA Helicases

Associated data

  • GENBANK/DQ181928