title: RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production.
abstract: Detection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3. Importance: The innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: De Jesus
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Su
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Danyang
authors.initials: D
authors.lastname: Gong
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wu
authors.affiliation: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA Interdepartmental Ph.D. Program in Bioinformatics, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wu
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA rsun@mednet.ucla.edu.
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
mesh_terms: D000818:Animals; D002460:Cell Line; D018142:Gammaherpesvirinae / Q000276:immunology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D017346:Protein Serine-Threonine Kinases; C534426:RIO kinase 3, human; C403191:TBK1 protein, human