Zhang Shengze, Luo Chuming, Chen Qiqi, Li Nina, Liao Xinzhong, Wu Jiani, Zha Haolu, Xie Ting, Bai Shaohui, Tian Weijian, Zhu Lin, Zou Xuan, Fang Shisong, Sun Caijun, Jiang Ying, Yuan Jianhui, Shu Yuelong, Wu Nan, Luo Huanle
School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, P.R. China.
School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, P.R. China.
iScience. 2024 Aug 20;27(9):110757. doi: 10.1016/j.isci.2024.110757. eCollection 2024 Sep 20.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.
肿瘤坏死因子受体相关因子6（TRAF6）在黄病毒感染中至关重要，它通过与病毒蛋白相互作用来调节宿主免疫反应。尽管其很重要，但TRAF6与寨卡病毒（ZIKV）之间的关系仍知之甚少。我们之前的蛋白质组学分析显示，与未感染的对照相比，ZIKV感染的人滋养层细胞中TRAF6蛋白水平降低。随后在细胞模型和小鼠组织中的研究证实，ZIKV感染后TRAF6的mRNA和蛋白水平均显著降低。进一步研究发现，ZIKV诱导P62介导的TRAF6降解，其中NS1被确定为主要促成因素。共定位和相互作用研究表明，NS1促进关键自噬介质P62与TRAF6的结合。值得注意的是，我们的研究结果显示TRAF6增强了ZIKV感染、NS1泛素化、NS1表达以及炎性细胞因子和趋化因子的产生。这些见解突出了TRAF6与ZIKV之间复杂的关系，为靶向NS1-TRAF6相互作用的药物有效控制ZIKV感染提供了可能性。
