Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response
Zhou Yu,
Taoyong Chen,
Xuelian Li,
Mingjin Yang,
Songqing Tang,
Xuhui Zhu,
Yan Gu,
Xiaoping Su,
Meng Xia,
Weihua Li,
Xuemin Zhang,
Qingqing Wang,
Xuetao Cao,
Jianli Wang
Affiliations
Zhou Yu
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
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
Xuelian Li
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
Mingjin Yang
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
Songqing Tang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
Xuhui Zhu
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
Yan Gu
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
Xiaoping Su
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China
Meng Xia
National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
Weihua Li
Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China
Xuemin Zhang
Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China
Qingqing Wang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
Xuetao Cao
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
Jianli Wang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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.
