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Hu Antigen R Regulates Antiviral Innate Immune Responses Through the Stabilization of Mrna for Polo-Like Kinase 2

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Hu Antigen R Regulates Antiviral Innate Immune Responses Through the Stabilization of Mrna for Polo-Like Kinase 2 Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2 This information is current as Takuya Sueyoshi, Takumi Kawasaki, Yuichi Kitai, Daisuke of October 2, 2021. Ori, Shizuo Akira and Taro Kawai J Immunol published online 20 April 2018 http://www.jimmunol.org/content/early/2018/04/19/jimmun ol.1701282 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/04/19/jimmunol.170128 Material 2.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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 20, 2018, doi:10.4049/jimmunol.1701282 The Journal of Immunology Hu Antigen R Regulates Antiviral Innate Immune Responses through the Stabilization of mRNA for Polo-like Kinase 2 Takuya Sueyoshi,* Takumi Kawasaki,* Yuichi Kitai,† Daisuke Ori,* Shizuo Akira,‡,x and Taro Kawai* Retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) play a critical role in inducing antiviral innate immune responses by activating IFN regulatory factor 3 (IRF3) and NF-kB, which regulates the transcription of type I IFN and inflammatory cytokines. Antiviral innate immune responses are also regulated by posttranscriptional and translational mechanisms. In this study, we identified an RNA-binding protein HuR as a regulator for RLR signaling. Overexpression of HuR, but not of other Hu members, increased IFN-b promoter activity. HuR-deficient mac- rophage cells exhibited decreased Ifnb1 expression after RLR stimulation, whereas they showed normal induction after stimu- lation with bacterial LPS or immunostimulatory DNA. Moreover, HuR-deficient cells displayed impaired nuclear translocation of Downloaded from IRF3 after RLR stimulation. In HuR-deficient cells, the mRNA expression of Polo-like kinase (PLK) 2 was markedly reduced. We found that HuR bound to the 39 untranslated region of Plk2 mRNA and increased its stabilization. PLK2-deficient cells also showed reduced IRF3 nuclear translocation and Ifnb mRNA expression during RLR signaling. Together, these findings suggest that HuR bolsters RLR-mediated IRF3 nuclear translocation by controlling the stability of Plk2 mRNA. The Journal of Immu- nology, 2018, 200: 000–000. nnate immune responses to virus infection are initiated upon 3 (IRF3). RLRs and cGAS use the mitochondrial protein IFN-b http://www.jimmunol.org/ the sensing of viral nucleic acid species by host pattern- promoter stimulator 1 (IPS-1) (also called MAVS) and the ER protein I recognition receptors, such as membrane-bound TLR3, STING as an adapter, respectively, which likewise culminates in the TLR7, and TLR9 and cytosolic proteins retinoic acid–inducible gene activation of NF-kB and IRF3 (3, 4). NF-kB largely regulates the I (RIG-I)–like receptors (RLRs) and cyclic GMP-AMP synthase expression of inflammatory cytokine genes, whereas IRF3 and IRF7 (cGAS). TLR3 and TLR7 sense dsRNA and ssRNA, respectively, regulate the expression of type I IFNs. whereas TLR9 senses DNA. The RLRs RIG-I and melanoma In the unstimulated condition, IRF3 is expressed in the cytoplasm. differentiation-associated gene 5 (MDA5) are cytoplasmic RNA After viral infection or other simulation, IRF3 is phosphorylated by ε helicases that sense viral RNA, and cGAS is a cytoplasmic sensor for the kinase TBK1 and/or its related kinase IKKi (also known as IKK ) by guest on October 2, 2021 DNA (1, 2). Upon ligand ligation, they activate downstream sig- (5). This phosphorylation induces conformational changes in IRF3, naling pathways, culminating in the induction of inflammatory cy- which result in the formation of an IRF3 homodimer and its sub- tokinesandtypeIIFNs.TLR7andTLR9areknowntoplaycentral sequent translocation into the nucleus, where it binds to target DNA roles in plasmacytoid dendritic cells (DCs) via the recruitment of the and upregulates the transcription of type I IFN genes. The activation adapter MyD88, which eventually activates the transcription factors of IRF3 is tightly regulated by multiple mechanisms. IRF3 binding NF-kB and IRF7. TLR3 is expressed in various cell types, including to the lipid phosphatidylinositol 5-phosphate, which is increased conventional DCs, macrophages, and nonimmune cells, and it uses upon viral infection, causes IRF3 to be phosphorylated by TBK1/ another adapter, TRIF, to activate NF-kB and IFN regulatory factor IKKi (6). The conjugation of the ubiquitin-like protein ISG15 by *Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate Address correspondence and reprint requests to Prof. Taro Kawai, Laboratory of School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute Nara 630-0192, Japan; †Department of Immunology, Graduate School of Pharma- of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan. ceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan; E-mail address: [email protected] ‡Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, x The online version of this article contains supplemental material. Suita, Osaka 565-0871, Japan; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan Abbreviations used in this article: avSG, antiviral SG; BMM, bone marrow–derived macrophage; CDS, coding sequence; cGAS, cyclic GMP-AMP synthase; DC, den- Received for publication September 6, 2017. Accepted for publication April 3, 2018. dritic cell; Elavl1, ELAV-like protein 1; G3BP, Ras-GAP SH3 domain binding pro- This work was supported by Japan Ministry of Education, Culture, Sports, Science tein; gRNA, guide RNA; HMW, high m.w.; IPS-1, IFN-b promoter stimulator 1; and Technology KAKENHI Grants-in-Aid for Research Activity (B) 26293107 and IRF3, IFN regulatory factor 3; ISD, IFN stimulatory DNA; KO, knockout; LMW, low 17H04066 (to T. Kawai) and Grants-in-Aid for Young Scientists (B) 17K15598 m.w.; MDA5, melanoma differentiation-associated gene 5; MEF, mouse embryonic (to T. Kawasaki) and 17K15726 (to D.O.). This work was also supported by the fibroblast; miRNA, microRNA; NDV, Newcastle disease virus; pGL3, pGL3- Uehara Memorial Foundation (to T. Kawai), the Takeda Science Foundation (to T. Kawai), Promoter Vector; pGL3-mPlk2 39UTR, pGL3-Promoter Vector harboring mouse the Joint Usage and Joint Research Programs, the Institute of Advanced Medical Plk2 39UTR; PLK, Polo-like kinase; poly(I:C), polyinosinic-polycytidylic acid; Sciences, Tokushima University (H27-28 to T. Kawai), and the Foundation for Nara RBP, RNA-binding protein; RIG-I, retinoic acid–inducible gene I; RLR, RIG-I–like Institute of Science and Technology (H28 to T. Kawai). receptor; RRM, RNA-recognition motif; RT-qPCR, real-time quantitative PCR; SG, stress granule; shRNA, short hairpin RNA; siRNA, small interfering RNA; UTR, T.S. performed the experiments. T.S., T. Kawasaki, Y.K., D.O., and T. Kawai untranslated region; W.B., Western blotting; WT, wild type. designed the experiments. S.A. contributed materials and tools. T.S., T. Kawasaki, and T. Kawai wrote the paper, and T. Kawai supervised the project. All authors Ó approved the final version of the manuscript. Copyright 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 The microarray data presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE103459. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701282 2 HuR REGULATES ANTIVIRAL INNATE IMMUNITY HERC5 is involved in sustained IRF3 activation (7). Additionally, intracellular stimulation. The transcriptional inhibitor actinomycin D was Polo-like kinase (PLK) 2 is associated with IRF3 nuclear transloca- purchased from Sigma-Aldrich. Newcastle disease virus (NDV) was pre- tion (8). In contrast, multiple proteins, including PIN1, YAP, RBCK1, pared as described previously (3). RAUL, PTEN, PP2A, MAPK phosphatase 5, SENP2, TRIM21 Plasmid construction a (Ro52), TRIM26, FoxO1, c-cbl, Rubicon, ERR ,MST1,andAGO2, Full-length mouse HuR, HuB, HuC, HuD, and PLK2 coding sequence (CDS) have been reported to negatively regulate IRF3 activation via distinct were amplified from murine brain, lung, and bone marrow cDNAs and mechanisms such as proteasome-dependent degradation, dephos- inserted into a pFlag-CMV-2 expression vector (Sigma-Aldrich). A series of phorylation, de-SUMOylation, and/or prevention of protein–protein mutants for HuR and PLK2 expression plasmids were generated by PCR from interactions (9–18). the full-length HuR pFlag-CMV-2 expression vector. For constructing the pGL3-Promoter
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