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Jimmunol.1801645.Full.Pdf FTRCA1, a Species-Specific Member of finTRIM Family, Negatively Regulates Fish IFN Response through Autophage-Lysosomal Degradation of TBK1 This information is current as of September 29, 2021. Min Wu, Xiang Zhao, Xiu-Ying Gong, Yang Wang, Jian-Fang Gui and Yi-Bing Zhang J Immunol published online 8 March 2019 http://www.jimmunol.org/content/early/2019/03/05/jimmun ol.1801645 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/03/05/jimmunol.180164 Material 5.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 by guest on September 29, 2021 *average 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 March 8, 2019, doi:10.4049/jimmunol.1801645 The Journal of Immunology FTRCA1, a Species-Specific Member of finTRIM Family, Negatively Regulates Fish IFN Response through Autophage-Lysosomal Degradation of TBK1 Min Wu,*,† Xiang Zhao,*,† Xiu-Ying Gong,*,† Yang Wang,*,† Jian-Fang Gui,*,†,‡ and Yi-Bing Zhang*,†,‡,x In mammals, tripartite motif (TRIM) proteins have emerged as pivotal players endowed with, directly, antiviral effects and, in- directly, modulatory capacity of the innate immune response. An unprecedented expansion of TRIM family has occurred in fish; however, the functional role of fish TRIM family members remains largely unknown. In this study, we identify a species-specific TRIM gene from crucian carp Carassius auratus, named FTRCA1, phylogenetically similar to the members of finTRIM, a subfamily of TRIM exclusively in teleost fish. FTRCA1 is induced by IFN and IFN stimuli as a typical IFN-stimulated gene. Downloaded from Overexpression of FTRCA1 negatively regulates IFN antiviral response by inhibition of IRF3 phosphorylation; consistently, knockdown of FTRCA1 results in enhanced levels of IRF3 phosphorylation and also IFN expression following poly(I:C) trans- fection. Whereas FTRCA1 is associated with several pivotal signaling molecules of RIG-I–like receptor pathway, its association with TBK1 results in autophage-lysosomal degradation of TBK1, thus abrogating the downstream IFN induction. Interestingly, FTRCA1 is phosphorylated by TBK1, but this phosphorylation is not required for downregulation of TBK1 protein. Transfection assays indicate that FTRCA1 is likely an E3 ligase with the requirement of RING finger domain, and deletion of N-terminal RING http://www.jimmunol.org/ domain or mutation of seven conservative sites abolishes the negative regulatory function of FTRCA1. Collectively, these results illuminate a novel finTRIM-mediated innate immune modulatory pathway, thus providing insights into species-specific regulation of fish IFN response. The Journal of Immunology, 2019, 202: 000–000. n mammals, virus infection rapidly induces production of pattern recognition receptors. Retinoic acid–inducible gene type I IFNs, such as IFN-a/b, upon the recognition of virus- I (RIG-I)–like receptors (RLRs) and several TLR have been well specific pathogen-associated molecular patterns by host characterized as sensors of viral-derived nucleic acids (1). Gen- I by guest on September 29, 2021 erally, they recognize intruding viral components, present at dif- ferent cellular compartments in immune cell lineages and other *State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of cell types, to trigger distinct signaling pathways, but finally con- Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; †Department of verge on the activation of cytosolic protein kinases, TANK-binding Aquaculture, University of Chinese Academy of Sciences, Wuhan 430072, China; ‡The Innovation Academy of Seed Design, Chinese Academy of Sciences, Wuhan kinase 1 (TBK1), which enables IFN regulatory factor (IRF) 3/7 to 430072, China; and xKey Laboratory of Aquaculture Disease Control of Ministry of translocate into the nucleus, turning on the transcription of IFN-a/b. Agriculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, The secreted IFNs in turn induce the expression of IFN-stimulated China genes (ISGs) through JAK-STAT pathway (1). Whilst IFNs are ORCID: 0000-0001-7647-9335 (Y.-B.Z.). curial for the establishment of host antiviral state, overproduction of Received for publication December 19, 2018. Accepted for publication February 14, IFNs leads to the development of immunopathological conditions; 2019. therefore, host cells develop multiple mechanisms to precisely This work was supported by a grant from the National Key R&D Program of China (2018YFD0900302), grants from the National Natural Science Foundation modulate the IFN signaling for appropriate production of IFNs (2). (31572646 and 31772875), and a grant from the Freshwater Ecology and Biotech- Emerging evidence highlights the pivotal roles of tripartite motif nology Laboratory (2016FBZ01). (TRIM) proteins in the innate antiviral response (2–4). TRIM The sequence presented in this article has been submitted to GenBank under acces- proteins are defined by a consecutive TRIM from the N to C sion number MK239647. terminus, a really interesting new gene (RING) zinc finger do- Address correspondence and reprint requests to Dr. Yi-Bing Zhang, State Key Lab- oratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, main, one or two B-boxes, and a coiled-coil domain, therefore also Chinese Academy of Sciences, Wuhan 430072, China. E-mail address: ybzhang@ihb. known as RBCC proteins (5). The RING domain has E3 ligase ac.cn activity responsible for the interaction with the ubiquitin- The online version of this article contains supplemental material. conjugating enzymes (E2) in the ubiquitination cascade process, Abbreviations used in this article: CAB, Crucian carp (C. auratus L.) blastula em- and the coiled-coil domain contributes to homo-interaction or bryonic; Co-IP, coimmunoprecipitation; EPC, epithelioma papulosum cyprini; oligomerization into high-order complexes (6). Mechanistically, a FTR, fish novel TRIM; GCRV, grass carp reovirus; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; MAVS, mitochondrial antiviral signaling protein; substantial number of TRIM proteins limit viral replication by MDA5, melanoma-differentiation–associated gene 5; MITA, mediator of IRF3 directly targeting viral proteins. For example, TRIM22 disrupts activation; NC, nontargeting control siRNA; ORF, open reading frame; poly(I:C), poly- inosinic:polycytidylic acid; RIG-I, retinoic acid–inducible gene I; RING, really the proper trafficking of HIV protein Gag (7); TRIM69 mediates interesting new gene; RLR, RIG-I–like receptor; RT-qPCR, quantitative real-time DENV nonstructural protein 3 polyubiquitination for proteasomal PCR; siRNA, small interfering RNA; TBK1, TANK-binding kinase 1; TRIM, degradation (8). A subset of TRIMs, including TRIM25 (9) tripartite motif. and TRIM26 (10, 11), modulate the innate antiviral signaling Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 to promote or abrogate the production of IFN, respectively. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801645 2 SPECIES-SPECIFIC REGULATION OF FISH IFN IMMUNE RESPONSE Interestingly, TRIM5a serves as not only a potent retroviral re- UV-inactivated GCRV-infected CAB cells (32), a pair of primers was striction factor against HIV but also a potential modulator of designed for RACE PCR to clone the full-length cDNA of crucian carp antiviral innate immunity (12), indicating the function complexity FTRCA1 (GenBank accession no. MK239647, https://www.ncbi.nlm. nih.gov/nuccore/MK239647). Primers used for RACE PCR are listed of TRIM proteins. in Supplemental Table I. Using the FTRCA1 sequence as baits, A genome-wide survey reveals a rapid expansion of TRIM protein BLAST search was performed against the genome database family in vertebrates (13–16), which seems linked to the in- from National Center for Biotechnology Information, including human, creasingly complex immune system (17). In line with the notion, Homo sapien;zebrafish,Danio rerio;fugu,Takifugu rubripes; puffer fish, Tetraodon nigroviridis;medaka,Oryzias latipes;grasscarp, 75 TRIM family members have been identified in human, whereas Ctenopharyngodon idella; common carp, Cyprinus carpio; and barbel, the fruitfly has only 7 and the worm 18 (13, 15). Functionally, Sinocyclocheilus grahami. Because there is relatively perfect integrity of more than one third of human TRIM genes are transcriptionally genome databases and comprehensive information of TRIM family in upregulated by IFNs (18), and roughly half contribute to regu- human and zebrafish (15, 16), the searched human and zebrafish ho- lating innate immune response (4). Similar expansion happens to mologs most homologous to FTRCA1 were further used as baits for protein BLAST against other genome data to obtain many more se- teleost fish, with over 100–120
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