1. Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland
2. Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland
3. MEMOREC Biotec GmbH, a Miltenyl Biotec company, Stoeckheimer Weg 1, D-50829 Koeln, Germany
4. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland
5. Department of Molecular Virology, University Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany

Correspondence to: Jürg Tschopp¹ Correspondence and requests for materials should be addressed to J.T. (Email: jurg.tschopp@unil.ch). The DNA sequence of human Cardif has been deposited in GenBank under accession number DQ181928.

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)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-B. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKK, IKK and IKK kinases by means of its C-terminal region, leading to the activation of NF-B and IRF3. Overexpression of Cardif results in interferon- and NF-B 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- production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.

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