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

doi:10.7554/eLife.14087

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

Elife. 2016 Apr 11:5:e14087. doi: 10.7554/eLife.14087.

Authors

Zhou Yu^{1

2

3}, Taoyong Chen², Xuelian Li², Mingjin Yang^{2

3}, Songqing Tang¹, Xuhui Zhu², Yan Gu², Xiaoping Su², Meng Xia³, Weihua Li⁴, Xuemin Zhang⁴, Qingqing Wang¹, Xuetao Cao^{2

3}, Jianli Wang¹

Affiliations

¹ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
² National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China.
³ National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
⁴ Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.

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.

Keywords: ASK1; Fbxo21; SCF complex; antiviral response; immunology; innate immunity; mouse; polyubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cullin Proteins / genetics
Cullin Proteins / immunology*
Disease Models, Animal
F-Box Proteins / genetics
F-Box Proteins / immunology*
Gene Expression Regulation
HEK293 Cells
Herpes Simplex / genetics
Herpes Simplex / immunology*
Herpes Simplex / virology
Herpesvirus 1, Human / immunology
Host-Pathogen Interactions
Humans
Immunity, Innate*
Interferon Type I / genetics
Interferon Type I / immunology
JNK Mitogen-Activated Protein Kinases / genetics
JNK Mitogen-Activated Protein Kinases / immunology
MAP Kinase Kinase Kinase 5 / genetics
MAP Kinase Kinase Kinase 5 / immunology*
Macrophages / immunology
Macrophages / virology
Mice
Mice, Inbred C57BL
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / immunology*
Signal Transduction
Vesicular Stomatitis / genetics
Vesicular Stomatitis / immunology*
Vesicular Stomatitis / virology
Vesiculovirus / immunology
Virus Replication / immunology
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / immunology

Substances

Cullin 1
Cullin Proteins
F-Box Proteins
Fbxo21 protein, mouse
Interferon Type I
S-Phase Kinase-Associated Proteins
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 5
Map3k5 protein, mouse

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.