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Noncanonical Role of FBXO6 in Regulating Antiviral Immunity

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Noncanonical Role of FBXO6 in Regulating Antiviral Immunity Noncanonical Role of FBXO6 in Regulating Antiviral Immunity Xiaohong Du, Fang Meng, Di Peng, Zining Wang, Wei Ouyang, Yu Han, Yayun Gu, Lingbo Fan, Fei Wu, Xiaodong This information is current as Jiang, Feng Xu and F. Xiao-Feng Qin of October 2, 2021. J Immunol published online 15 July 2019 http://www.jimmunol.org/content/early/2019/07/12/jimmun ol.1801557 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/07/12/jimmunol.180155 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 15, 2019, doi:10.4049/jimmunol.1801557 The Journal of Immunology Noncanonical Role of FBXO6 in Regulating Antiviral Immunity Xiaohong Du,*,†,1 Fang Meng,*,†,1 Di Peng,*,†,1 Zining Wang,‡,1 Wei Ouyang,x Yu Han,x Yayun Gu,*,† Lingbo Fan,*,† Fei Wu,*,† Xiaodong Jiang,{ Feng Xu,x,2 and F. Xiao-Feng Qin*,†,2 The evolutionarily conserved F-box family of proteins are well known for their role as the key component of SKP1–Cullin1–F-box (SCF) E3 ligase in controlling cell cycle, cell proliferation and cell death, carcinogenesis, and cancer metastasis. However, thus far, there is only limited investigation on their involvement in antiviral immunity. In contrast to the canonical function of FBXO6 associated with SCF E3 ligase complex, we report, in this study, that FBXO6 can also potently regulate the activation of IFN-I signaling during host response to viral infection by targeting the key transcription factor IFN-regulatory factor 3 (IRF3) for accelerated degradation independent of SCF in human embryonic kidney cells (HEK293T) and human lung cancer epithelial cells Downloaded from (A549). Structure and function delineation has further revealed that FBXO6 interacts with IAD domain of IRF3 through its FBA region to induce ubiquitination and degradation of IRF3 without the involvement of SCF. Thus, our studies have identified a general but, to our knowledge, previously unrecognized role and a novel noncanonical mechanism of FBXO6 in modulating IFN-I–mediated antiviral immune responses, which may protect the host from immunopathology of overreactive and harmful IFN-I production. The Journal of Immunology, 2019, 203: 000–000. http://www.jimmunol.org/ ype I IFNs (IFN-I), including IFN-a and IFN-b, are The homeostasis of IFN-I and balanced IFN-I response is critical critical antiviral innate cytokines that can activate both for the health of the body. When production of IFN-I is insufficient, T innate and adaptive immune responses. Upon viral in- the virus is difficult to be eliminated, leading to chronic infectious fection, host pattern-recognition receptors (PRRs), including diseases (4–6). However, prolonged activation of cellular antiviral TLRs, RLRs, and DNA sensors, sense pathogen-associated mo- responses might produce aberrant and unwanted amounts of lecular patterns (PAMPs), therefore triggering the activation of IFN-I, leading to autoimmune inflammatory diseases (6–9). As the antiviral immunity (1). The activation signals emanated from essential component of IFN-I signaling, regulation of IRF3 is PRRs are subsequently transduced by multiple adaptor molecules, critical for maintaining the homeostasis of IFN-I production in like TIR domain–containing, adapter-inducing IFN-b (TRIF), host cells (10). Phosphatase PP2A has been reported to recruit its by guest on October 2, 2021 mitochondrial antiviral signaling protein (MAVS), and stimulator adaptor protein RACK1 to promote the dephosphorylation of IRF3 of IFN genes (STING), and converged on the activation of TANK- (11). Furthermore, Phosphatase and tensin homolog (PTEN) with binding kinase 1 (TBK1) or IKB kinase ε (IKKε or IKKi). Further phosphatase activity can negatively regulate IRF3 phosphorylation downstream of the pathway, TBK1 coordinates with IKKi to phos- at Ser-97 to block its import to nucleus (12). In addition to phorylate IFN-regulatory factor 3 (IRF3), leading to the translocation phosphorylation, nuclear receptor-binding SET domain 3 (NSD3) of phosphorylated IRF3 from cytoplasm to nucleus to induce IFN-I has been identified as the lysine methyltransferase that methylate gene expression (1–3). IRF3 at K366, enhancing the transcription activity of IRF3 (13). *Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy Drug Development of China (Grant 2015ZX09102023), and the National Grand of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Foreign Experts Projects (Culture and Education) (Grant GDW20181100054). †Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China; ‡Collaborative X.D., F.M., D.P., Z.W., W.O., Y.H., Y.G., L.F., and F.W. performed the experiments; Innovation Center of Cancer Medicine, Department of Experimental Medicine, State Key X.D., F.M., D.P., Z.W., X.J., F.X., and F.X.-F.Q. analyzed data and wrote the man- Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, Guangdong x uscript; and F.X. and F.X.-F.Q. were responsible for research design, strategy, and 510275, China; Department of Infectious Diseases, Second Affiliated Hospital of Zhejiang { supervision. University School of Medicine, Hangzhou, Zhejiang 310009, China; and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 Address correspondence and reprint requests to Prof. F. Xiao-Feng Qin or Prof. Feng Xu, Suzhou Institute of Systems Medicine, No. 100 Chongwen Road, Suzhou, 1X.D., F.M., D.P., and Z.W. contributed equally to this work. Jiangsu 215123, China (F.X.-F.Q.) or Department of Infectious Diseases, Second 2F.X. and F.X.-F.Q. contributed equally to this work. Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang 310009, China (F.X.). E-mail addresses: [email protected] ORCIDs: 0000-0003-2856-9058 (Z.W.); 0000-0001-5764-6628 (F.X.); 0000-0002- (F.X.-F.Q.) or [email protected] (F.X.) 5395-0304 (F.X.-F.Q.). The online version of this article contains supplemental material. Received for publication November 26, 2018. Accepted for publication June 11, 2019. Abbreviations used in this article: BiLC, bimolecular luminescence complementa- tion; CHX, cycloheximide; Co-IP, coimmunoprecipitation; HA, hemagglutinin; This work was supported by the Chinese Academy for Medical Sciences Initiative IFN-I, type I IFN; IRF3, IFN-regulatory factor 3; ISG, IFN-stimulated gene; ISRE, for Innovative Medicine (Grant 2016-I2M-1-005), the National Natural Science IFN stimulation response element; KO, knockout; poly(dA:dT), poly(deoxyadenylic- Foundation of China (Grants 81701567, 81773058, and 31800726), the Jiangsu deoxythymidylic) acid; poly(I:C), polyinosinic:polycytidylic acid; SCF, SKP1– Provincial Natural Science Foundation (Grants BK20151252 and BK20171232), Cullin1–F-box; SeV, Sendai virus; sgRNA, short-guide RNA; siRNA, small interfering the Fund of Jiangsu Provincial Science and Technology Department (Grant RNA; TBK1, TANK-binding kinase 1; VSV, vesicular stomatitis virus; VSV-eGFP, BM2016006), the Fund of the Suzhou Municipal Science and Technology Bureau VSV with enhanced GFP; WT, wild-type. (Grant SZS201716), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (Grant 2017NL31002), the Key Program for Innovative Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801557 2 FBXO6 AND ANTIVIRAL IMMUNITY Another study also reported that viral infection could enhance Angeles, CA). HRP/anti-Flag (M2) was obtained from Sigma-Aldrich. the binding of protein arginine methyltransferases 6 (PRMT6) to HRP/antihemagglutinin was obtained from Roche. HRP/anti–b-actin was IRF3, thus inhibiting the interaction between IRF3 and TBK1 obtained from GenScript. Anti-IRF3 and anti-FBXO6 were obtained from Santa Cruz Biotechnology. Ab specific to IRF3 phosphorylated at residue (14). In conjunction to the interaction, C-terminal phosphoryla- Ser396 was obtained from Cell Signaling Technology. tion of IRF-3 appears to facilitate IRF3 proteasomal degradation (15). After stimulation by dsRNA, induced phosphorylation of the Constructs and plasmids Ser339/Pro340 motif of IRF3 led to its interaction with pepti- The constructs coding for FBXO6, IRF3, and truncated mutants were cloned dylprolyl isomerase Pin1 and, finally, polyubiquitination and then into pcDNA3.1 vector. The expression plasmids encoding RIG-I (2 card), proteasome-dependent degradation of IRF3 (16). RTA-associated IKKi, IRF3, IRF3-5D, and hemagglutinin (HA)-Ub were provided by Dr. J. Cui (University of Sun Yat-sen, Guangzhou, China). ubiquitin ligase (RAUL), a HECT domain ubiquitin E3 ligase, limited IFN-I production
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