title: Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection.
abstract: By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-αβ induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I-like receptors, and cGAS/STING signaling pathways. Accordingly, knocking down of CK2 expression or genetic ablation of its kinase activity resulted in elevated IFN-αβ response in response to infection by DNA and RNA viruses. Moreover, PP2A was identified as one of the intermediate phosphatases responsible for CK2-regulated IFN response, suggesting that CK2 may regulate TBK1 and IRF3 activation indirectly. Importantly, blockade of CK2 activity by small molecule inhibitor was able to activate TBK1, whereby eliciting effective host defense mechanisms against hepatitis C virus infection. Taken together, our results identify CK2 as a novel regulator of TBK1 and IRF3 and suggest that targeting CK2 by small molecular inhibitor may be a viable approach to prevent and treat viral infections.
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Min
authors: M
authors: Du
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Jinghua
authors: J
authors: Liu
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Xia
authors: X
authors: Chen
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Yadong
authors: Y
authors: Xie
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Chuanping
authors: C
authors: Yuan
authors: Unit of Viral Hepatitis, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Yu
authors: Y
authors: Xiang
authors: Unit of Molecular Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Bing
authors: B
authors: Sun
authors: Unit of Tumor Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Ke
authors: K
authors: Lan
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, China;
authors: Mingzhou
authors: M
authors: Chen
authors: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Immunology Program, Life Sciences Institute, National University of Singapore, Singapore 117597; and.
authors: Sharmy J
authors: SJ
authors: James
authors: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Immunology Program, Life Sciences Institute, National University of Singapore, Singapore 117597; and.
authors: Yongliang
authors: Y
authors: Zhang
authors: Unit of Viral Hepatitis, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
authors: Jin
authors: J
authors: Zhong
authors: Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China huixiao@ips.ac.cn.
authors: Hui
authors: H
authors: Xiao
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000099197:STING Protein
chemical_list: D047390:Casein Kinase II; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse