E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses

Yinjing Song; Lihua Lai; Zhenlu Chong; Jia He; Yuanyuan Zhang; Yue Xue; Yiwei Xie; Songchang Chen; Ping Dong; Luoquan Chen; Zhimin Chen; Feng Dai; Xiaopeng Wan; Peng Xiao; Xuetao Cao; Yang Liu; Qingqing Wang

doi:10.1038/ncomms14654

E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses

Nat Commun. 2017 Mar 13:8:14654. doi: 10.1038/ncomms14654.

Authors

Yinjing Song¹, Lihua Lai¹, Zhenlu Chong¹, Jia He¹, Yuanyuan Zhang², Yue Xue¹, Yiwei Xie¹, Songchang Chen¹, Ping Dong³, Luoquan Chen¹, Zhimin Chen², Feng Dai¹, Xiaopeng Wan¹, Peng Xiao¹, Xuetao Cao^{1

4}, Yang Liu¹, Qingqing Wang¹

Affiliations

¹ Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
² The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
³ Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China.

Abstract

Viruses can escape from host recognition by degradation of RIG-I or interference with the RIG-I signalling to establish persistent infections. However, the mechanisms by which host cells stabilize RIG-I protein for avoiding its degradation are largely unknown. We report here that, upon virus infection, the E3 ubiquitin ligase FBXW7 translocates from the nucleus into the cytoplasm and stabilizes RIG-I. FBXW7 interacts with SHP2 and mediates the degradation and ubiquitination of SHP2, thus disrupting the SHP2/c-Cbl complex, which mediates RIG-I degradation. When infected with VSV or influenza A virus, FBXW7 conditional knockout mice (Lysm⁺FBXW7^f/f) show impaired antiviral immunity. FBXW7-deficient macrophages have decreased RIG-I protein levels and type-I interferon signalling. Furthermore, PBMCs from RSV-infected children have reduced FBXW7 mRNA levels. Our results identify FBXW7 as an important interacting partner for RIG-I. These findings provide insights into the function of FBXW7 in antiviral immunity and its related clinical significance.

Publication types

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

MeSH terms

Active Transport, Cell Nucleus
Animals
Child
DEAD Box Protein 58 / genetics*
DEAD Box Protein 58 / immunology
F-Box-WD Repeat-Containing Protein 7 / deficiency
F-Box-WD Repeat-Containing Protein 7 / genetics*
F-Box-WD Repeat-Containing Protein 7 / immunology
Gene Expression Regulation
HEK293 Cells
Host-Pathogen Interactions*
Humans
Influenza A virus / immunology*
Influenza A virus / pathogenicity
Interferon Type I / genetics
Interferon Type I / immunology
Macrophages / immunology*
Macrophages / virology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Primary Cell Culture
Protein Stability
Protein Transport
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / immunology
Proteolysis
Proto-Oncogene Proteins c-cbl / genetics
Proto-Oncogene Proteins c-cbl / immunology
RAW 264.7 Cells
Respiratory Syncytial Viruses / immunology*
Respiratory Syncytial Viruses / pathogenicity
Ubiquitination
Vesiculovirus / immunology*
Vesiculovirus / pathogenicity

Substances

F-Box-WD Repeat-Containing Protein 7
Fbxw7 protein, mouse
Interferon Type I
Proto-Oncogene Proteins c-cbl
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Ptpn11 protein, mouse
Ddx58 protein, mouse
DEAD Box Protein 58
Cbl protein, mouse