title: DDX60 Is Involved in RIG-I-Dependent and Independent Antiviral Responses, and Its Function Is Attenuated by Virus-Induced EGFR Activation.
abstract: RIG-I-mediated type I interferon (IFN) production and nuclease-mediated viral RNA degradation are essential for antiviral innate immune responses. DDX60 is an IFN-inducible cytoplasmic helicase. Here, we report that DDX60 is a sentinel for both RIG-I activation and viral RNA degradation. We show that DDX60 is an upstream factor of RIG-I that activates RIG-I signaling in a ligand-specific manner. DDX60 knockout attenuates RIG-I signaling and significantly reduces virus-induced type I IFN production in vivo. In addition, we show that DDX60 is involved in RIG-I-independent viral RNA degradation. DDX60 and RIG-I adaptor MAVS double-knockout mice reveal a role for DDX60-dependent RNA degradation in antiviral responses. Several viruses induced DDX60 phosphorylation via epidermal growth factor receptor (EGFR), leading to attenuation of the DDX60 antiviral activities. Our results define DDX60 as a sentinel for cytoplasmic antiviral response, which is counteracted by virus-mediated EGF receptor activation.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan. Electronic address: oshiumi@med.hokudai.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshiumi
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0246, Japan.
authors.forename: Moeko
authors.initials: M
authors.lastname: Miyashita
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Research Center for Infection-Associated Cancer, Division of Disease Model Innovation, Institute of Genetic Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morioka
authors.affiliation: Research Institute for Microbial Disease, Osaka University, 3-1 Yamadaoka Suita, Osaka 565-0871, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D040262:Receptors, Vascular Endothelial Growth Factor / Q000276:immunology*; D015398:Signal Transduction; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016898:Interferon-alpha; D012367:RNA, Viral; D011971:Receptors, Immunologic; D040262:Receptors, Vascular Endothelial Growth Factor; C452820:RIGI protein, human; C561888:DDX60 protein, human; C561889:DDX60 protein, mouse; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases