title: Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates.
abstract: Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.
authors.affiliation: Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Goubau
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlee
authors.affiliation: Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Safia
authors.initials: S
authors.lastname: Deddouche
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Pruijssers
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Goldeck
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schuberth
authors.affiliation: Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Annemarthe G
authors.initials: AG
authors.lastname: Van der Veen
authors.affiliation: Instituto de Biología Funcional y Genómica. Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Zacarías González 2, 37007, Salamanca, Spain.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Rehwinkel
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Iskarpatyoti
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Janos
authors.initials: J
authors.lastname: Ludwig
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Caetano
authors.initials: C
authors.lastname: Reis e Sousa
mesh_terms: D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism*; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012087:Reoviridae / Q000235:genetics* / Q000276:immunology* / Q000502:physiology
chemical_list: D011756:Diphosphates; D012367:RNA, Viral; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases