title: E3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses.
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+FBXW7f/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.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Yinjing
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Lai
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Chong
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.affiliation: The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Songchang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Luoquan
authors.initials: L
authors.lastname: Chen
authors.affiliation: The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Wan
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.|National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002648:Child; D000071457:DEAD Box Protein 58 / Q000235:genetics* / Q000276:immunology; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D055550:Protein Stability; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000276:immunology; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology; D000067996:RAW 264.7 Cells; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000472:pathogenicity; D054875:Ubiquitination; D018116:Vesiculovirus / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D007370:Interferon Type I; D050721:Proto-Oncogene Proteins c-cbl; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; C493849:Cbl protein, mouse