title: DYRK2 Negatively Regulates Type I Interferon Induction by Promoting TBK1 Degradation via Ser527 Phosphorylation.
abstract: Viral infection activates the transcription factors NF-κB and IRF3, which contribute to the induction of type I interferons (IFNs) and cellular antiviral responses. Protein kinases play a critical role in various signaling pathways by phosphorylating their substrates. Here, we identified dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) as a negative regulator of virus-triggered type I IFN induction. DYRK2 inhibited the virus-triggered induction of type I IFNs and promoted the K48-linked ubiquitination and degradation of TANK-binding kinase 1 (TBK1) in a kinase-activity-dependent manner. We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1. These findings suggest that DYRK2 negatively regulates virus-triggered signaling by targeting TBK1 for phosphorylation and priming it for degradation, and these data provide new insights into the molecular mechanisms that dictate the cellular antiviral response.
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China; The College of Basic Medical Science, Shaanxi University of Chinese Medicine, Xi'an, China.
authors.forename: Tai
authors.initials: T
authors.lastname: An
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Po
authors.initials: P
authors.lastname: Tien
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.affiliation: The College of Life Sciences, State Key Laboratory of Virology, Modern Virology Research Center, Wuhan University, Wuhan, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering; D012694:Serine / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D007370:Interferon Type I; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D012694:Serine; D000097603:Dyrk Kinases; C403191:TBK1 protein, human