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Cardif: A protein central to innate immunity is inactivated by the HCV NS3 serine protease
Author(s) -
Evans Jared D.,
Seeger Christoph
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21096
Subject(s) - irf3 , rig i , biology , signal transducing adaptor protein , tlr3 , interferon , interferon regulatory factors , mda5 , virology , rna silencing , small interfering rna , ns3 , innate immune system , rna helicase a , rna interference , rna , microbiology and biotechnology , helicase , signal transduction , toll like receptor , hepatitis c virus , gene , receptor , virus , biochemistry
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 1.) 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‐κB. Here we describe Cardif, a new CARD‐containing adaptor protein that interacts with RIG‐I and recruits IKK‐α, IKK‐β and IKK‐ϵ kinases by means of its C‐terminal region, leading to the activation of NF‐κB and IRF3. Overexpression of Cardif results in interferon‐β and NF‐κB 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‐β production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG‐I to the initiation of antiviral programmes.