TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3.
TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3.
复制标题
DOI：
10.1371/journal.ppat.1004726
复制
发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Wang P;Zhao W;Zhao K;Zhang L;Gao C
病毒感染导致转录因子IRF 3的激活和随后的I型干扰素的产生，其诱导称为干扰素刺激基因（ISG）的各种抗病毒基因的转录以消除病毒感染。IRF 3的活化需要磷酸化、二聚化和核转位。然而，终止IRF 3在细胞核中激活的机制尚不清楚。在这里，我们报告了TRIM 26通过靶向核IRF 3来负调节IFN-β产生和抗病毒反应的鉴定。TRIM 26与IRF 3结合并促进其在细胞核中的K48连接的多聚泛素化和降解。TRIM 26降解WT IRF 3和组成型活性突变体IRF 3 5D，但不降解磷酸化缺陷突变体IRF 3 5A。此外，核定位信号（NLS）中的IRF 3突变体不能进入细胞核，不被TRIM 26降解。重要的是，病毒感染促进TRIM 26核转位，这是IRF 3降解所必需的。因此，TRIM 26减弱了TLR 3/4、RLR和DNA传感途径下游的IFN-β启动子活化和IFN-β产生。TRIM 26转基因小鼠表现出更少的IRF 3激活和IFN-β产生，而增加病毒复制。我们的研究结果描绘了一个新的机制，终止IRF 3激活细胞核通过TRIM 26介导的IRF 3泛素化和降解。天然免疫是保护宿主免受入侵病原体感染的第一道防线。由先天免疫细胞产生的I型干扰素是细胞抗病毒免疫应答的关键。病毒感染后，IFN-β转录需要IRF 3，IRF 3通过磷酸化、二聚化和核转位被激活。尽管IRF 3活化和IFN-β产生对于宿主预防病毒感染是必需的，但异常或过量的IFN-β产生可能导致人类自身免疫性疾病的发病机制。因此，IRF 3激活和IFN-β产生必须在病毒感染后的适当时间点终止。IRF 3在细胞核中的降解代表了终止IFN-β产生的新机制。在这里，我们鉴定了TRIM 26作为靶向核IRF 3的新型E3连接酶。TRIM 26通过多聚泛素化和核IRF 3的降解减弱IFN-β的产生。TRIM 26转基因小鼠的体内实验进一步证实了TRIM 26对IFN-β产生和抗病毒应答的负功能。鉴于IRF 3是TLR 3、RLRs和细胞内DNA信号通路下游的常见分子，我们的研究确定了限制RNA和DNA病毒诱导的信号传导、炎症和组织损伤的新机制，并为治疗自身免疫性疾病提供了新的线索。
Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear translocation. However, the mechanisms for the termination of IRF3 activation in nucleus are elusive. Here we report the identification of TRIM26 to negatively regulate IFN-β production and antiviral response by targeting nuclear IRF3. TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. TRIM26 degraded WT IRF3 and the constitutive active mutant IRF3 5D, but not the phosphorylation deficient mutant IRF3 5A. Furthermore, IRF3 mutant in the Nuclear Localization Signal (NLS), which could not move into nucleus, was not degraded by TRIM26. Importantly, virus infection promoted TRIM26 nuclear translocation, which was required for IRF3 degradation. As a consequence, TRIM26 attenuated IFN-β promoter activation and IFN-β production downstream of TLR3/4, RLR and DNA sensing pathways. TRIM26 transgenic mice showed much less IRF3 activation and IFN-β production, while increased virus replication. Our findings delineate a novel mechanism for the termination of IRF3 activation in nucleus through TRIM26-mediated IRF3 ubiquitination and degradation. Innate immunity is the first line of defense to protect host from infection of invading pathogens. Production of type I inteferons by the innate immune cells is pivotal for the cellular antiviral immune responses. After virus infection, IFN-β transcription requires IRF3, which is activated through phosphorylation, dimerization and nuclear translocation. Although IRF3 activation and IFN-β production are essential for the host to prevent viral infection, aberrant or excessive IFN-β production may lead to the pathogenesis of human autoimmune diseases. Therefore, IRF3 activation and IFN-β production must be terminated at the appropriate time points after viral infection. Degradation of IRF3 in the nucleus represents a novel mechanism to terminate IFN-β production. Here we identified TRIM26 as a novel E3 ligase to target nuclear IRF3. TRIM26 attenuated IFN-β production through polyubiquitination and degradation of nuclear IRF3. In vivo experiments with TRIM26 transgenic mice further confirmed the negative function of TRIM26 on IFN-β production and antiviral responses. Given that IRF3 is a common molecule downstream of TLR3, RLRs and intracellular DNA signaling pathways, our study identified a novel mechanism to limit RNA and DNA virus-induced signaling, inflammation and tissue injury and provided new clues for the treatment of autoimmune diseases.
登录
查看更多内容
影响因子：
3.4
作者：
Sardiello M;Cairo S;Fontanella B;Ballabio A;Meroni G
通讯作者：
Meroni G
DOI：
10.1038/nri2413
发表时间：
2008-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Ozato K;Shin DM;Chang TH;Morse HC 3rd
通讯作者：
Morse HC 3rd
影响因子：
30.5
作者：
Saitoh, Tatsuya;Tun-Kyi, Adrian;Yamaoka, Shoji
通讯作者：
Yamaoka, Shoji
影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S