title: Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7.
abstract: IFN regulatory factor 7 (IRF7) is a potent transcription factor of type I IFNs and IFN-stimulated genes and is known as the master regulator of type I IFN-dependent immune responses. Because excessive responses could harm the host, IRF7 itself is delicately regulated at the transcriptional, translational, and posttranslational levels. Modification of IRF7 by small ubiquitin-related modifiers (SUMOs) has been shown to regulate IFN expression and antiviral responses negatively, but the specific E3 ligase needed for IRF7 SUMOylation has remained unknown. As reported in this article, we have identified the tripartite motif-containing protein 28 (TRIM28) as a binding partner of IRF7. We have demonstrated that TRIM28 also interacts with the SUMO E2 enzyme and increases SUMOylation of IRF7 both in vivo and in vitro, suggesting it acts as a SUMO E3 ligase of IRF7. Unlike the common SUMO E3 ligase, protein inhibitor of activated STAT1, the E3 activity of TRIM28 is specific to IRF7, because it has little effect on IRF7's close relative IRF3. TRIM28 is therefore, so far as we know, the first IRF7-specific SUMO E3 reported. TRIM28-mediated SUMOylation of IRF7 is increased during viral infection, and SUMOylation of transcription factors usually results in transcriptional repression. Overexpression of TRIM28 therefore inhibits IRF7 transactivation activity, whereas knockdown of TRIM28 has the opposite effect and potentiates IFN production and antiviral responses. Collectively, our results suggest that TRIM28 is a specific SUMO E3 ligase and negative regulator of IRF7.
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liang
authors.forename: Hongying
authors.initials: H
authors.lastname: Deng
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Li
authors.forename: Xianfang
authors.initials: X
authors.lastname: Wu
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Tang
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chang
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Fanxiu
authors.initials: F
authors.lastname: Zhu
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry / Q000502:physiology*; D013379:Substrate Specificity / Q000276:immunology; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
chemical_list: D050839:Interferon Regulatory Factor-7; D012097:Repressor Proteins; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases