Publication Date:
2014-08-15
Description:
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-alpha and beta; 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201573/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201573/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goubau, Delphine -- Schlee, Martin -- Deddouche, Safia -- Pruijssers, Andrea J -- Zillinger, Thomas -- Goldeck, Marion -- Schuberth, Christine -- Van der Veen, Annemarthe G -- Fujimura, Tsutomu -- Rehwinkel, Jan -- Iskarpatyoti, Jason A -- Barchet, Winfried -- Ludwig, Janos -- Dermody, Terence S -- Hartmann, Gunther -- Reis e Sousa, Caetano -- A3598/Cancer Research UK/United Kingdom -- MC_UU_12010/8/Medical Research Council/United Kingdom -- R01 AI038296/AI/NIAID NIH HHS/ -- R37 AI038296/AI/NIAID NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2014 Oct 16;514(7522):372-5. doi: 10.1038/nature13590. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2]. ; 1] Institut fur Klinische Chemie und Klinische Pharmakologie, Universitatsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany [2]. ; 1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Drosophila Genetics and Epigenetics, Laboratory of Developmental Biology, CNRS UMR7622, Universite Pierre et Marie Curie, Paris, France (S.D.); Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK (J.R.). ; 1] Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [2] Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA. ; Institut fur Klinische Chemie und Klinische Pharmakologie, Universitatsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany. ; Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Instituto de Biologia Funcional y Genomica. Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Zacarias Gonzalez 2, 37007, Salamanca, Spain. ; 1] Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [2] Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA [3] Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232-2581, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119032" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Base Pairing
;
Base Sequence
;
DEAD-box RNA Helicases/*metabolism
;
Diphosphates/*metabolism
;
Female
;
Genome, Viral/genetics
;
*Immunity, Innate
;
Male
;
Mice
;
RNA, Viral/*chemistry/genetics/*metabolism
;
Reoviridae/*genetics/*immunology/physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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