title: Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I.
abstract: The cytoplasmic RNA helicase RIG-I mediates innate sensing of RNA viruses. The genomes of influenza A virus (FLUAV) are encapsidated by the nucleoprotein and associated with RNA polymerase, posing potential barriers to RIG-I sensing. We show that RIG-I recognizes the 5'-triphosphorylated dsRNA on FLUAV nucleocapsids but that polymorphisms at position 627 of the viral polymerase subunit PB2 modulate RIG-I sensing. Compared to mammalian-adapted PB2-627K, avian FLUAV nucleocapsids possessing PB2-627E are prone to increased RIG-I recognition, and RIG-I-deficiency partially restores PB2-627E virus infection of mammalian cells. Heightened RIG-I sensing of PB2-627E nucleocapsids correlates with previously established lower affinity of 627E-containing PB2 for nucleoprotein and is increased by further nucleocapsid instability. The effect of RIG-I on PB2-627E nucleocapsids is independent of antiviral signaling, suggesting that RIG-I-nucleocapsid binding alone can inhibit infection. These results indicate that RIG-I is a direct avian FLUAV restriction factor and highlight nucleocapsid disruption as an antiviral strategy.
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Weber
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Sediri
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Felgenhauer
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Binzen
authors.affiliation: Department of Cell Biology and Cell Pathology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bänfer
authors.affiliation: Department of Cell Biology and Cell Pathology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.affiliation: Institute for Virology, University Medical Center, D-79008 Freiburg, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Brunotte
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Institute for Virology, University Medical Center, D-79008 Freiburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.affiliation: Institute for Virology, University Medical Center, D-79008 Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwemmle
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.affiliation: Institute for Virology, Philipps-University Marburg, D-35043 Marburg, Germany. Electronic address: friedemann.weber@staff.uni-marburg.de.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Weber
mesh_terms: D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D019251:Nucleocapsid / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D009975:Orthomyxoviridae; D011485:Protein Binding; D012330:RNA, Double-Stranded / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D011971:Receptors, Immunologic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D050505:Mutant Proteins; C057027:PB2 protein, Influenzavirus A; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases