Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.
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.
Meylan
Etienne
E
Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Curran
Joseph
J
Hofmann
Kay
K
Moradpour
Darius
D
Binder
Marco
M
Bartenschlager
Ralf
R
Tschopp
Jürg
J
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases; D011971:Receptors, Immunologic; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C494233:Irf3 protein, mouse; C505371:MAVS protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C452820:RIGI protein, human