Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
J Immunol. 2011 Nov 1;187(9):4754-63. doi: 10.4049/jimmunol.1101704. Epub 2011 Sep 21.
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.
干扰素调节因子 7（IRF7）是 I 型干扰素和干扰素刺激基因的有效转录因子，被称为 I 型干扰素依赖性免疫反应的主调控因子。因为过度反应可能会伤害宿主，IRF7 本身在转录、翻译和翻译后水平上受到精细调节。已经表明，IRF7 的小泛素相关修饰物（SUMO）的修饰负调控 IFN 的表达和抗病毒反应，但用于 IRF7 SUMOylation 的特定 E3 连接酶仍然未知。正如本文所报道的，我们已经确定三肽重复蛋白 28（TRIM28）是 IRF7 的结合伴侣。我们已经证明，TRIM28 还与 SUMO E2 酶相互作用，并在体内和体外均增加 IRF7 的 SUMOylation，表明它作为 IRF7 的 SUMO E3 连接酶发挥作用。与常见的 SUMO E3 连接酶，即激活 STAT1 的蛋白抑制剂不同，TRIM28 的 E3 活性是针对 IRF7 的，因为它对 IRF7 的近亲 IRF3 几乎没有影响。TRIM28 因此，据我们所知，是迄今为止报道的第一个 IRF7 特异性 SUMO E3。TRIM28 介导的 IRF7 SUMOylation 在病毒感染期间增加，并且转录因子的 SUMOylation通常导致转录抑制。因此，TRIM28 的过表达抑制了 IRF7 的转录激活活性，而 TRIM28 的敲低则产生相反的效果，增强了 IFN 的产生和抗病毒反应。总之，我们的结果表明 TRIM28 是 IRF7 的特异性 SUMO E3 连接酶和负调控因子。
