title: A Novel Function of F-Box Protein FBXO17 in Negative Regulation of Type I IFN Signaling by Recruiting PP2A for IFN Regulatory Factor 3 Deactivation.
abstract: The F-box proteins were originally identified as the key component of SKP1-Cullin1-F-box E3 ligase complexes that control the stability of their specific downstream substrates essential for cell growth and survival. However, the involvement of these proteins in type I IFN (IFN-I) signaling during innate immunity has not been investigated. In this study we report that the F-box protein FBXO17 negatively regulates IFN-I signaling triggered by double-strand DNA, RNA, or viral infection. We found that FBXO17 specifically interacts with IFN regulatory factor 3 (IRF3) and decreases its dimerization and nuclear translocation. The decrease of IRF3 dimerization and nuclear translocation is due to the recruitment of protein phosphatase 2 (PP2A) mediated by FBXO17, resulting in IRF3 dephosphorylation. Interestingly, PP2A recruitment does not require the F-box domain but instead the F-box associated region of the protein; thus, the recruitment is independent of the canonical function of the SKP1-Cullin1-F-box family of E3 ligase. Together, our studies identify a previously unreported role of FBXO17 in regulating IFN-I signaling and further demonstrate a novel mechanism for IRF3 deactivation by F-box protein-mediated recruitment of PP2A.
authors.affiliation: State Key Laboratory of Biocontrol, Sun Yat-Sen University, Guangzhou 510275, China.|Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Di
authors.initials: D
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biocontrol, Sun Yat-Sen University, Guangzhou 510275, China.|Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Zining
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; and Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.
authors.forename: Anfei
authors.initials: A
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biocontrol, Sun Yat-Sen University, Guangzhou 510275, China; fqin1@foxmail.com zhaoy82@mail.sysu.edu.cn.|Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; and Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China fqin1@foxmail.com zhaoy82@mail.sysu.edu.cn.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D044783:F-Box Proteins / Q000276:immunology* / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000276:immunology* / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D044783:F-Box Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D054648:Protein Phosphatase 2