title: Expression of the immune regulator tripartite-motif 21 is controlled by IFN regulatory factors.
abstract: Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ-activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element-dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4(-/-) cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren's syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ-mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1(-/-) cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.
authors: Unit of Rheumatology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors: Maria
authors: M
authors: Sjöstrand
authors: Aurélie
authors: A
authors: Ambrosi
authors: Susanna
authors: S
authors: Brauner
authors: Jenna
authors: J
authors: Sullivan
authors: Stephen
authors: S
authors: Malin
authors: Vijay K
authors: VK
authors: Kuchroo
authors: Alexander
authors: A
authors: Espinosa
authors: Marie
authors: M
authors: Wahren-Herlenius
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D023061:Gene Order; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D020218:Response Elements; D012261:Ribonucleoproteins / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D012261:Ribonucleoproteins; D050794:STAT1 Transcription Factor; D000099207:SS-A Antigen