title: Incoming RNA virus nucleocapsids containing a 5'-triphosphorylated genome activate RIG-I and antiviral signaling.
abstract: Host defense to RNA viruses depends on rapid intracellular recognition of viral RNA by two cytoplasmic RNA helicases: RIG-I and MDA5. RNA transfection experiments indicate that RIG-I responds to naked double-stranded RNAs (dsRNAs) with a triphosphorylated 5' (5'ppp) terminus. However, the identity of the RIG-I stimulating viral structures in an authentic infection context remains unresolved. We show that incoming viral nucleocapsids containing a 5'ppp dsRNA "panhandle" structure trigger antiviral signaling that commences with RIG-I, is mediated through the adaptor protein MAVS, and terminates with transcription factor IRF-3. Independent of mammalian cofactors or viral polymerase activity, RIG-I bound to viral nucleocapsids, underwent a conformational switch, and homo-oligomerized. Enzymatic probing and superresolution microscopy suggest that RIG-I interacts with the panhandle structure of the viral nucleocapsids. These results define cytoplasmic entry of nucleocapsids as the proximal RIG-I-sensitive step during infection and establish viral nucleocapsids with a 5'ppp dsRNA panhandle as a RIG-I activator.
authors.affiliation: Institute for Virology, Philipps-University Marburg, 35043 Marburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Weber
authors.forename: Ali
authors.initials: A
authors.lastname: Gawanbacht
authors.forename: Matthias
authors.initials: M
authors.lastname: Habjan
authors.forename: Andreas
authors.initials: A
authors.lastname: Rang
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Anna Mareike
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Sophie
authors.initials: S
authors.lastname: Veitinger
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Devignot
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Friedemann
authors.initials: F
authors.lastname: Weber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016679:Genome, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D019251:Nucleocapsid / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011122:Polyphosphates / Q000378:metabolism; D012327:RNA Virus Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000821:virology; D012328:RNA Viruses / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011122:Polyphosphates; D012367:RNA, Viral; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; C005692:triphosphoric acid