Incoming RNA virus nucleocapsids containing a 5′-triphosphorylated genome activate RIG-I and antiviral signaling

Michaela Weber, Ali Gawanbacht, Matthias Habjan, Andreas Rang, Christoph Borner, Anna Mareike Schmidt, Sophie Veitinger, Ralf Jacob, Stéphanie Devignot, Georg Kochs, Adolfo García-Sastre, Friedemann Weber

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

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.

Original languageEnglish
Pages (from-to)336-346
Number of pages11
JournalCell Host and Microbe
Volume13
Issue number3
DOIs
StatePublished - 13 Mar 2013

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