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5367.Full-Text.Pdf Tripartite Motif (TRIM) 12c, a Mouse Homolog of TRIM5, Is a Ubiquitin Ligase That Stimulates Type I IFN and NF-κB Pathways along with TNFR-Associated This information is current as Factor 6 of September 26, 2021. Tsung-Hsien Chang, Ryusuke Yoshimi and Keiko Ozato J Immunol 2015; 195:5367-5379; Prepublished online 26 October 2015; doi: 10.4049/jimmunol.1402064 Downloaded from http://www.jimmunol.org/content/195/11/5367 Supplementary http://www.jimmunol.org/content/suppl/2015/10/24/jimmunol.140206 http://www.jimmunol.org/ Material 4.DCSupplemental References This article cites 55 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/195/11/5367.full#ref-list-1 Why The JI? Submit online. by guest on September 26, 2021 • 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 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Tripartite Motif (TRIM) 12c, a Mouse Homolog of TRIM5, Is a Ubiquitin Ligase That Stimulates Type I IFN and NF-kB Pathways along with TNFR-Associated Factor 6 Tsung-Hsien Chang,*,† Ryusuke Yoshimi,* and Keiko Ozato* Tripartite motif (TRIM) protein TRIM5 of the primate species restricts replication of HIV and other retroviruses. Whereas pri- mates have a single TRIM5 gene, the corresponding locus in the mouse has expanded during evolution, now containing more than eight related genes. Owing to the complexity of the genomic organization, a mouse homolog of TRIM5 has not been fully studied thus far. In the present study, we report that Trim12c (formerly Trim12-2) encodes a TRIM5-like protein with a ubiquitin ligase activity. Similar to the primate TRIM5, TRIM12c is expressed in the cytoplasm as a punctate structure and induced upon IFN and pathogen stimulation in macrophages and dendritic cells. We show that TRIM12c interacts with TRAF6, a key protein in the pathogen rec- Downloaded from ognition receptor signaling, and reciprocally enhances their ubiquitination, leading to cooperative activation of IFN and NF-kB pathways. This study identifies TRIM12c as a mouse TRIM5 equivalent, critical for host innate immunity. The Journal of Immunology, 2015, 195: 5367–5379. roteins of the tripartite motif (TRIM) superfamily are upon the host (14). Similar to many other TRIM proteins, TRIM5 of conserved throughout metazoans and play diverse bio- primates and other species is induced by IFNs, resulting in enhanced P logical roles (1–3). Many TRIM proteins have character- antiretroviral activity (15, 16). In addition to TRIM5, other proteins in http://www.jimmunol.org/ istic four-domain composition with the RING, B box, coiled-coil, the TRIM cluster have been shown to inhibit early and late stages of and PRY/SPRY (B30.2) domains. The N-terminal RING domain retroviral life cycle (17, 18). Besides retroviral restriction, a number is attributed to a putative ubiquitin ligase activity, and the of TRIM proteins, including those in the TRIM cluster, play pivotal C-terminal PRY/SPRY domain is associated with retroviral restriction. roles in host defense through pathogen recognition receptor (PRR) A number of TRIM genes are tandemly arrayed in a genomic andRIG-I/MDAsignalingtoregulateNF-kB and IFN pathways (19– region designated the TRIM cluster on chromosome 7 in mice and 23). Some of these TRIM proteins interact with cytoplasmic adaptors chromosome 11 in humans. Of the TRIM cluster members, TRIM5a or kinases such as TAK1 or IKKs to regulate activity of NF-kBand (hereafter TRIM5) has been intensely studied, partly because IFN regulatory factor (IRF) 3/7 (24–28). by guest on September 26, 2021 rehesus monkey TRIM5 was shown to potently restrict HIV life The TRIM5 locus of the mouse genome poses interesting, un- cycle (4–6). TRIM5 in humans, cows, and rabbits also carries solved issues on the evolution of antipathogen activity associated antiretroviral activities, which is accounted for by the SPRY domain with the TRIM family. Unlike humans and primates that have a (7–13). Although humanTRIM5 has a weak activity to restrict HIV single TRIM5 gene, this locus has expanded in the mouse genome, replication, a recent report showed that it interacts with TAK1 kinases now harboring more than eight Trim5-like genes within a ∼250-kb to activate NF-kB pathway and confers a generalized antiviral state DNA stretch, called the Trim5 group, that is located between Trim6 and Trim66 of the Trim cluster (29, 30) (see Fig. 1A). This *Program in Genomics of Differentiation, National Institute of Child Health and expansion is thought to be a result of gene duplication and positive Human Development, National Institutes of Health, Bethesda MD, 20892; and selection for enhanced antiviral activities (29, 30). Partly owing † Department of Medical Education and Research, Kaohsiung Veterans General to the complexity of genomic organization and the presence of Hospital, Kaohsiung, Taiwan, 81362 multiple Trim genes in this region, a functional mouse homolog of ORCIDs: 0000-0003-4806-7864 (T.-H.C.); 0000-0002-3945-307X (R.Y.). TRIM5 has not been clearly identified so far. For similar reasons, Received for publication August 13, 2014. Accepted for publication October 5, 2015. only a few Trim5 group genes, such as Trim30a, have been ex- This work was supported in part by Kaohsiung Veterans General Hospital Grant VGHKS102-004 and by Ministry of Science and Technology, Taiwan Grants NSC amined for function (20, 31). 99-2320-B-075B-005 and MOST 104-2320-B-075B-005. In this study, we cloned a full-length Trim12c cDNA, among Address correspondence and reprint requests to Prof. Keiko Ozato, National Institutes other genes mapped to the Trim5 group. TRIM12c protein has a of Health, National Institute of Child Health and Human Development, Program in typical four-domain composition and is structurally very similar to Genomics of Differentiation, 6 Center Drive, Building 6, Room 2A01, Bethesda MD, 20892-2753. E-mail address: [email protected] TRIM5 of primates and other species. Trim12c is induced by IFNs The online version of this article contains supplemental material. and viral infection in macrophages and dendritic cells (DCs), and the protein displays characteristic cytoplasmic localization similar Abbreviations used in this article: BM, bone marrow; BMDC, bone marrow–derived DC; CpG, CpG oligodeoxynucleotide 1826; DC, dendritic cell; HA, hemagglutinin; to TRIM5. We show that TRIM12c is a ubiquitin ligase that can HA-Ub, HA-tagged ubiquitin; IRF, IFN regulatory factor; KDR, knockdown-resistant; interact with TNFR-associated factor (TRAF) 6, a central regulator MCMV, mouse CMV; NDV, Newcastle disease virus; poly(I:C), polyinosinic- polycytidylic acid; PRR, pattern recognition receptor; qRT-PCR, quantitative of NF-kB and IFN pathways. This interaction enhanced ubiq- RT-PCR; shRNA, short hairpin RNA; TRAF, TNFR-associated factor; TRIM, uitination of both proteins, leading to increased activation of type tripartite motif. IIFNandNF-kB pathways. Collectively, this study identifies This article is distributed under The American Association of Immunologists, Inc., TRIM12c as a mouse homolog of TRIM5 with E3 ubiquitin Reuse Terms and Conditions for Author Choice articles. ligase activity through which it activates proinflammatory and Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 IFN responses. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402064 5368 MURINE TRIM12C ACTIVATES INNATE IMMUNITY Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 FIGURE 1. Induction of Trim cluster genes in macrophages and DCs. (A) Schematic diagram of the Trim cluster genes and the Trim5 group region in the mouse genome. The Trim cluster encompasses ∼17 Mb in chromosome 7 (gray bar). The Trim5 region is expanded in the mouse genome to form the Trim5 group, which contains 11 Trim genes within the ∼250-kb space (blue bars with each gene in red). In this study, Trim12c has (Figure legend continues) The Journal of Immunology 5369 Materials and Methods Extracts (20 mg) were resolved on 4–12% NuPAGE (Invitrogen) or 10% Cells and reagents SDS-PAGE for immunoblotting. For ubiquitination assays, 293T cells were transfected with the expression vector for HA-ubiquitin (35) and RAW 264.7 cells (ATCC TIB-71), 293T cells (ATCC CRL-1660) and TRIM12c or TRAF6 for 30 h. Extract preparations and immunoblotting NIH3T3 cells (ATCC CRL-1658) were grown in DMEM supplemented used for ubiquitination assays were described previously (32, 36). Briefly, with 10% FBS. Bone marrow (BM)-derived macrophages and BM-derived extracts were prepared from cells incubated with 20 mM MG132 in the last DCs (BMDCs) from C57BL/6 mice were grown in the presence of M-CSF 4hin400ml SDS buffer (2% SDS, 50 mM Tris-HCl [pH 7.5], 20
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