{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:01:27Z","timestamp":1790388087167,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,6,1]],"date-time":"2009-06-01T00:00:00Z","timestamp":1243814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The tripartite motif (TRIM) family member, TRIM21, is an E3 ubiquitin ligase for IFN regulatory factor (IRF)3 and IRF8 that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52\/SS-A. The function of TRIM21 in vivo, however, has remained elusive. We generated Trim21\u2212\/\u2212 mice with the Trim21 gene replaced by an enhanced GFP (EGFP) reporter. EGFP expression analyses showed that Trim21 was widely expressed in many tissues, with the highest levels in immune cells. Studies of Trim21\u2212\/\u2212 embryonic fibroblasts demonstrated that TLR-mediated induction of proinflammatory cytokines, including IL-1\u03b2, IL-6, TNF-\u03b1, and CXCL10, was consistently up-regulated relative to wild-type cells. Reporter analyses demonstrated that TLR-mediated NF-\u03baB activation was higher in Trim21\u2212\/\u2212 cells than in wild-type cells, most likely accounting for their enhanced cytokine expression. In contrast, functional analyses of immune cells from Trim21\u2212\/\u2212 mice revealed no abnormalities in their composition or function, even though ubiquitylation of IRF3 and IRF8 was impaired. These results suggested possible redundancies in activities mediated by TRIM21. In keeping with this concept, we found that a number of TRIM family members were up-regulated in Trim21\u2212\/\u2212 cells. Taken together, these findings demonstrate that TRIM21 plays a previously unrecognized role in the negative regulation of NF-\u03baB-dependent proinflammatory cytokine responses, and suggest that multiple TRIM proteins contribute to the maintenance of functional equilibrium in inflammatory responses, in part through functional redundancy.<\/jats:p>","DOI":"10.4049\/jimmunol.0804121","type":"journal-article","created":{"date-parts":[[2009,6,3]],"date-time":"2009-06-03T20:48:22Z","timestamp":1244062102000},"page":"7527-7538","source":"Crossref","is-referenced-by-count":147,"title":["Gene Disruption Study Reveals a Nonredundant Role for TRIM21\/Ro52 in NF-\u03baB-Dependent Cytokine Expression in Fibroblasts"],"prefix":"10.1093","volume":"182","author":[{"given":"Ryusuke","family":"Yoshimi","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Hsien","family":"Chang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD 20852"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Atsumi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Herbert C","family":"Morse","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD 20852"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Ozato","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,6,15]]},"reference":[{"key":"2025032715465806600_R1","first-page":"2140","article-title":"The tripartite motif family identifies cell compartments.","volume-title":"EMBO J.","year":"2001"},{"key":"2025032715465806600_R2","first-page":"799","article-title":"TRIM family proteins: retroviral restriction and antiviral defense.","volume-title":"Nat. Rev. Microbiol.","year":"2005"},{"key":"2025032715465806600_R3","first-page":"849","article-title":"TRIM family proteins and their emerging roles in innate immunity.","volume-title":"Nat. Rev. Immunol.","year":"2008"},{"key":"2025032715465806600_R4","first-page":"e16","article-title":"TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.","volume-title":"PLoS Pathog.","year":"2008"},{"key":"2025032715465806600_R5","first-page":"619","article-title":"Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells.","volume-title":"Eur. J. Immunol.","year":"2008"},{"key":"2025032715465806600_R6","first-page":"246","article-title":"The 52 000 MW Ro\/SS-A autoantigen in Sjogren\u2019s syndrome\/systemic lupus erythematosus (Ro52) is an interferon-\u03b3 inducible tripartite motif protein associated with membrane proximal structures.","volume-title":"Immunology","year":"2002"},{"key":"2025032715465806600_R7","first-page":"220","article-title":"Interferon-\u03b1 induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies.","volume-title":"J. Clin. Immunol.","year":"2007"},{"key":"2025032715465806600_R8","first-page":"26","article-title":"Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032715465806600_R9","first-page":"1560","article-title":"A 52-kD protein is a novel component of the SS-A\/Ro antigenic particle.","volume-title":"J. Exp. Med.","year":"1988"},{"key":"2025032715465806600_R10","first-page":"1233","article-title":"A serologic marker for fetal risk of congenital heart block.","volume-title":"Arthritis Rheum.","year":"2002"},{"key":"2025032715465806600_R11","first-page":"183","article-title":"The mapping of the human 52-kD Ro\/SSA autoantigen gene to human chromosome 11, and its polymorphisms.","volume-title":"Am. J. Hum. Genet.","year":"1993"},{"key":"2025032715465806600_R12","first-page":"204","article-title":"Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci.","volume-title":"Nat. Genet.","year":"2008"},{"key":"2025032715465806600_R13","first-page":"6277","article-title":"The Sjogren\u2019s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032715465806600_R14","first-page":"620","article-title":"Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain.","volume-title":"Scand. J. Immunol.","year":"1999"},{"key":"2025032715465806600_R15","first-page":"591","article-title":"Autoantigen Ro52 directly interacts with human IgG heavy chain in vivo in mammalian cells.","volume-title":"Mol. Immunol.","year":"2000"},{"key":"2025032715465806600_R16","first-page":"2045","article-title":"Ro52 functionally interacts with IgG1 and regulates its quality control via the ERAD system.","volume-title":"Mol. Immunol.","year":"2008"},{"key":"2025032715465806600_R17","first-page":"5994","article-title":"Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein.","volume-title":"Mol. Cell. Biol.","year":"2006"},{"key":"2025032715465806600_R18","first-page":"415","article-title":"Autoantigen Ro52 is an E3 ubiquitin ligase.","volume-title":"Biochem. Biophys. Res. Commun.","year":"2006"},{"key":"2025032715465806600_R19","first-page":"1780","article-title":"The E3 ubiquitin ligase Ro52 negatively regulates IFN-\u03b2 production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.","volume-title":"J. Immunol.","year":"2008"},{"key":"2025032715465806600_R20","first-page":"6200","article-title":"Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.","volume-title":"Proc. Natl. Acad. Sci. 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Immunol.","year":"2003"},{"key":"2025032715465806600_R24","first-page":"961","article-title":"ICSBP\/IRF-8 retrovirus transduction rescues dendritic cell development in vitro.","volume-title":"Blood","year":"2003"},{"key":"2025032715465806600_R25","first-page":"1354","article-title":"The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-\u03baB p50 homodimers.","volume-title":"Genes Dev.","year":"1993"},{"key":"2025032715465806600_R26","first-page":"155","article-title":"ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages.","volume-title":"Immunity","year":"2000"},{"key":"2025032715465806600_R27","first-page":"2573","article-title":"IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity.","volume-title":"J. 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Immunol.","year":"2008"},{"key":"2025032715465806600_R31","first-page":"10736","article-title":"Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2025032715465806600_R32","first-page":"147","article-title":"The interleukin 12 p40 gene promoter is primed by interferon \u03b3 in monocytic cells.","volume-title":"J. Exp. Med.","year":"1996"},{"key":"2025032715465806600_R33","first-page":"460","article-title":"Signaling to NF-\u03baB by Toll-like receptors.","volume-title":"Trends Mol. Med.","year":"2007"},{"key":"2025032715465806600_R34","first-page":"24","article-title":"TLR signaling.","volume-title":"Semin. Immunol.","year":"2007"},{"key":"2025032715465806600_R35","first-page":"1601","article-title":"Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.","volume-title":"J. Exp. Med.","year":"2008"},{"key":"2025032715465806600_R36","first-page":"3782","article-title":"TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response.","volume-title":"J. Immunol.","year":"2009"},{"key":"2025032715465806600_R37","first-page":"916","article-title":"TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.","volume-title":"Nature","year":"2007"},{"key":"2025032715465806600_R38","first-page":"8970","article-title":"Subclassification of the RBCC\/TRIM superfamily reveals a novel motif necessary for microtubule binding.","volume-title":"J. Biol. Chem.","year":"2006"},{"key":"2025032715465806600_R39","first-page":"356","article-title":"Fibroblast biology: effector signals released by the synovial fibroblast in arthritis.","volume-title":"Arthritis Res.","year":"2000"},{"key":"2025032715465806600_R40","first-page":"431","article-title":"Nuclear factor-\u03baB in cancer development and progression.","volume-title":"Nature","year":"2006"},{"key":"2025032715465806600_R41","first-page":"1351","article-title":"Two waves of nuclear factor \u03baB recruitment to target promoters.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2025032715465806600_R42","first-page":"395","article-title":"NF-\u03baB activation: nondegradative ubiquitination implicates NEMO.","volume-title":"Trends Immunol.","year":"2006"},{"key":"2025032715465806600_R43","first-page":"369","article-title":"TRIM30\u03b1 negatively regulates TLR-mediated NF-\u03baB activation by targeting TAB2 and TAB3 for degradation.","volume-title":"Nat. Immunol.","year":"2008"},{"key":"2025032715465806600_R44","first-page":"1072","article-title":"The Ret finger protein inhibits signaling mediated by the noncanonical and canonical I\u03baB kinase family members.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032715465806600_R45","first-page":"801","article-title":"The tumor suppressor CYLD negatively regulates NF-\u03baB signalling by deubiquitination.","volume-title":"Nature","year":"2003"},{"key":"2025032715465806600_R46","first-page":"797","article-title":"Loss of the cylindromatosis tumor suppressor inhibits apoptosis by activating NF-\u03baB.","volume-title":"Nature","year":"2003"},{"key":"2025032715465806600_R47","first-page":"2131","article-title":"The sequestosome 1\/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6\/NF-\u03baB activity.","volume-title":"J. Immunol.","year":"2009"},{"key":"2025032715465806600_R48","first-page":"6783","article-title":"Essential role of sequestosome 1\/p62 in regulating accumulation of Lys63-ubiquitinated proteins.","volume-title":"J. Biol. Chem.","year":"2008"},{"key":"2025032715465806600_R49","first-page":"95","article-title":"Signal integration and diversification through the p62 scaffold protein.","volume-title":"Trends Biochem. Sci.","year":"2007"},{"key":"2025032715465806600_R50","first-page":"1682","article-title":"Abnormal NF-\u03baB activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression.","volume-title":"J. Immunol.","year":"1999"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/12\/7527\/62688098\/9143.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/12\/7527\/62688098\/9143.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T16:50:11Z","timestamp":1743353411000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/12\/7527\/8007191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,6]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2009,6,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0804121","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,6]]},"published":{"date-parts":[[2009,6]]}}}