title: Lys29-linkage of ASK1 by Skp1-Cullin 1-Fbxo21 ubiquitin ligase complex is required for antiviral innate response.
abstract: Protein ubiquitination regulated by ubiquitin ligases plays important roles in innate immunity. However, key regulators of ubiquitination during innate response and roles of new types of ubiquitination (apart from Lys48- and Lys63-linkage) in control of innate signaling have not been clearly understood. Here we report that F-box only protein Fbxo21, a functionally unknown component of SCF (Skp1-Cul1-F-box protein) complex, facilitates Lys29-linkage and activation of ASK1 (apoptosis signal-regulating kinase 1), and promotes type I interferon production upon viral infection. Fbxo21 deficiency in mice cells impairs virus-induced Lys29-linkage and activation of ASK1, attenuates c-Jun N-terminal kinase (JNK) and p38 signaling pathway, and decreases the production of proinflammatory cytokines and type I interferon, resulting in reduced antiviral innate response and enhanced virus replication. Therefore Fbxo21 is required for ASK1 activation via Lys29-linkage of ASK1 during antiviral innate response, providing mechanistic insights into non-proteolytic roles of SCF complex in innate immune response.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.|National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.|National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Taoyong
authors.identifier: 0000-0002-2507-0027
authors.initials: T
authors.lastname: Chen
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.|National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Mingjin
authors.initials: M
authors.lastname: Yang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Songqing
authors.initials: S
authors.lastname: Tang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Zhu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.|National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D054243:Vesicular Stomatitis / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018116:Vesiculovirus / Q000276:immunology; D014779:Virus Replication / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; C000620174:Fbxo21 protein, mouse; D007370:Interferon Type I; D044786:S-Phase Kinase-Associated Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: ASK1; Fbxo21; SCF complex; antiviral response; immunology; innate immunity; mouse; polyubiquitination