title: DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation.
abstract: RIG-I is a DExD/H-box RNA helicase and functions as a critical cytoplasmic sensor for RNA viruses to initiate antiviral interferon (IFN) responses. Here we demonstrate that another DExD/H-box RNA helicase DHX36 is a key molecule for RIG-I signaling by regulating double-stranded RNA (dsRNA)-dependent protein kinase (PKR) activation, which has been shown to be essential for the formation of antiviral stress granule (avSG). We found that DHX36 and PKR form a complex in a dsRNA-dependent manner. By forming this complex, DHX36 facilitates dsRNA binding and phosphorylation of PKR through its ATPase/helicase activity. Using DHX36 KO-inducible MEF cells, we demonstrated that DHX36 deficient cells showed defect in IFN production and higher susceptibility in RNA virus infection, indicating the physiological importance of this complex in host defense. In summary, we identify a novel function of DHX36 as a critical regulator of PKR-dependent avSG to facilitate viral RNA recognition by RIG-I-like receptor (RLR).
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Ji-Seung
authors.initials: JS
authors.lastname: Yoo
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto, Japan.
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Takahasi
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Chen Seng
authors.initials: CS
authors.lastname: Ng
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Ouda
authors.affiliation: Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Onomoto
authors.affiliation: Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yoneyama
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Janice Ching
authors.initials: JC
authors.lastname: Lai
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Lattmann
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nagamine
authors.affiliation: Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Iwabuchi
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
mesh_terms: D003594:Cytoplasmic Granules / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D012327:RNA Virus Infections / Q000276:immunology*; D012328:RNA Viruses / Q000276:immunology; D012330:RNA, Double-Stranded / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013312:Stress, Physiological; D014162:Transfection; D019892:eIF-2 Kinase / Q000276:immunology*
chemical_list: D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D019892:eIF-2 Kinase; C452820:RIGI protein, human; C466988:DHX36 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases