title: Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.
abstract: Alpha/beta interferon immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We directly compared the innate immune signaling requirements of representative viruses of the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Reoviridae for RIG-I, MDA5, and interferon promoter-stimulating factor 1 (IPS-1). In cultured fibroblasts, IPS-1 was essential for innate immune signaling of downstream interferon regulatory factor 3 activation and interferon-stimulated gene expression, but the requirements for RIG-I and MDA5 were variable. Each was individually dispensable for signaling triggered by reovirus and dengue virus, whereas RIG-I was essential for signaling by influenza A virus, influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified cellular genes triggered during influenza A virus infection whose expression was strictly dependent on RIG-I and which are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation associated with the host response to contemporary and pandemic strains of influenza virus. These results define IPS-1-dependent signaling as an essential feature of host immunity to RNA virus infection. Our observations further demonstrate differential and redundant roles for RIG-I and MDA5 in pathogen recognition and innate immune signaling that may reflect unique and shared biologic properties of RNA viruses whose differential triggering and control of gene expression may impact pathogenesis and infection.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Box 357650, Seattle, WA 98195-7650, USA.
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Loo
authors.forename: Jamie
authors.initials: J
authors.lastname: Fornek
authors.forename: Nanette
authors.initials: N
authors.lastname: Crochet
authors.forename: Gagan
authors.initials: G
authors.lastname: Bajwa
authors.forename: Olivia
authors.initials: O
authors.lastname: Perwitasari
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Sobrido
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Gill
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D018067:Flaviviridae / Q000276:immunology; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000096:biosynthesis; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology; D010252:Paramyxoviridae / Q000276:immunology; D012328:RNA Viruses / Q000276:immunology*; D012087:Reoviridae / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D000072640:Interferon-Induced Helicase, IFIH1; C512612:MAVS protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse