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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Animals
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Antiviral Agents / immunology
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Antiviral Agents / metabolism*
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Cell Line
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Hepacivirus / enzymology
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Hepacivirus / immunology
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Hepacivirus / metabolism*
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Humans
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I-kappa B Kinase
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Interferon Regulatory Factor-3
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Interferon-beta / biosynthesis
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Interferon-beta / genetics
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Interferon-beta / immunology
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Mice
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Molecular Sequence Data
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NF-kappa B / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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RNA Helicases / immunology
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RNA Helicases / metabolism*
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Receptors, Immunologic
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Substrate Specificity
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Viral Nonstructural Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antiviral Agents
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DNA-Binding Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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MAVS protein, human
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NF-kappa B
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NS3 protein, hepatitis C virus
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Receptors, Immunologic
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Transcription Factors
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Viral Nonstructural Proteins
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Interferon-beta
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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RNA Helicases