Lys29-linkage of ASK1 by Skp1−Cullin 1−Fbxo21 ubiquitin ligase complex is required for antiviral innate response

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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.

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Zhou Yu

Zhejiang University School of Medicine, Institute of Immunology, Hangzhou, China

Competing interests
No competing interests declared.
Taoyong Chen

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

For correspondence
chenty@immunol.org

Competing interests
No competing interests declared.
Xuelian Li

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

Competing interests
No competing interests declared.
Mingjin Yang

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

Competing interests
No competing interests declared.
Songqing Tang

Zhejiang University School of Medicine, Institute of Immunology, Hangzhou, China

Competing interests
No competing interests declared.
Xuhui Zhu

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

Competing interests
No competing interests declared.
Yan Gu

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

Competing interests
No competing interests declared.
Xiaoping Su

Second Military Medical University, National Key Laboratory of Medical Immunology and Institute of Immunology, Shanghai, China

Competing interests
No competing interests declared.
Meng Xia

Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, National Key Laboratory of Medical Molecular Biology and Department of Immunology, Beijing, China

Competing interests
No competing interests declared.
Weihua Li

National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing, China

Competing interests
No competing interests declared.
Xuemin Zhang

National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing, China

Competing interests
No competing interests declared.
Qingqing Wang

Zhejiang University School of Medicine, Institute of Immunology, Hangzhou, China

Competing interests
No competing interests declared.
Xuetao Cao

National Key Laboratory of Medical Immunology and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

Competing interests
Xuetao Cao, Reviewing editor, eLife.
Jianli Wang

Zhejiang University School of Medicine, Institute of Immunology, Hangzhou, China

Competing interests
No competing interests declared.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and was approved by the Scientific Investigation Board of Second Military Medical University, Shanghai (Case No. SMMU-2015-0067).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.