Jia Xue, Zhou Hongli, Wu Chao, Wu Qiankun, Ma Shichao, Wei Congwen, Cao Ye, Song Jingdong, Zhong Hui, Zhou Zhuo, Wang Jianwei
MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100850, China; and.
J Immunol. 2017 Jun 15;198(12):4652-4658. doi: 10.4049/jimmunol.1601322. Epub 2017 May 5.
Tripartite motif-containing 14 (TRIM14) is a mitochondrial adaptor that facilitates innate immune signaling. Upon virus infection, the expression of TRIM14 is significantly induced, which stimulates the production of type-I IFNs and proinflammatory cytokines. As excessive immune responses lead to harmful consequences, TRIM14-mediated signaling needs to be tightly balanced. In this study, we identify really interesting new gene-type zinc finger protein 125 (RNF125) as a negative regulator of TRIM14 in the innate antiviral immune response. Overexpression of RNF125 inhibits TRIM14-mediated antiviral response, whereas knockdown of RNF125 has the opposite effect. RNF125 interacts with TRIM14 and acts as an E3 ubiquitin ligase that catalyzes TRIM14 ubiquitination. RNF125 promotes K48-linked polyubiquitination of TRIM14 and mediates its degradation via the ubiquitin-proteasome pathway. Consequently, wild-type mouse embryonic fibroblasts show significantly reduced TRIM14 protein levels in late time points of viral infection, whereas TRIM14 protein is retained in RNF125-deficient mouse embryonic fibroblasts. Collectively, our data suggest that RNF125 plays a new role in innate immune response by regulating TRIM14 ubiquitination and degradation.
含三联基序蛋白14（TRIM14）是一种促进天然免疫信号传导的线粒体衔接蛋白。病毒感染后，TRIM14的表达显著上调，刺激I型干扰素和促炎细胞因子的产生。由于过度的免疫反应会导致有害后果，因此TRIM14介导的信号传导需要严格平衡。在本研究中，我们鉴定出真有趣新基因型锌指蛋白125（RNF125）是天然抗病毒免疫反应中TRIM14的负调节因子。RNF125的过表达抑制TRIM14介导的抗病毒反应，而敲低RNF125则产生相反的效果。RNF125与TRIM14相互作用，并作为一种E3泛素连接酶催化TRIM14的泛素化。RNF125促进TRIM14的K48连接的多聚泛素化，并通过泛素-蛋白酶体途径介导其降解。因此，野生型小鼠胚胎成纤维细胞在病毒感染后期的TRIM14蛋白水平显著降低，而TRIM14蛋白则保留在RNF125缺陷的小鼠胚胎成纤维细胞中。总的来说，我们的数据表明RNF125通过调节TRIM14的泛素化和降解在天然免疫反应中发挥新作用。
