Zhou Peng, Zhang Qingxiang, Yang Yueshan, Liu Dan, Wu Wanrong, Jongkaewwattana Anan, Jin Hui, Zhou Hongbo, Luo Rui
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
PLoS Pathog. 2025 May 28;21(5):e1013200. doi: 10.1371/journal.ppat.1013200. eCollection 2025 May.
Tembusu virus (TMUV), an emerging avian orthoflavivirus, causes severe economic losses due to egg-drop syndrome and fatal encephalitis in domestic waterfowl. To combat this threat, the host immune system plays a crucial role in controlling and eliminating TMUV infection. Understanding the mechanisms of this immune response is thus vital for developing effective strategies against the virus. In this study, we investigated the antiviral activities of duck TRIM family proteins (duTRIM) against TMUV, focusing particularly on duTRIM14 as a potent host restriction factor. We showed that overexpression of duTRIM14 significantly inhibits TMUV replication, while its deficiency leads to increased viral titers. We elucidate a novel mechanism by which duTRIM14 interacts with the TMUV NS1 protein, facilitating its K27/K29-linked polyubiquitination and subsequent proteasomal degradation. The Lys141 residue on NS1 was identified as critical for this process, with its removal significantly enhancing TMUV replication both in vitro and in vivo. Furthermore, we showed that duTRIM14 interacts with duck TBK1 (duTBK1), promoting its K63-linked polyubiquitination on Lys30 and Lys401, which substantially augments IFN-β production during TMUV infection. Taken together, these results provide a novel dual-action antiviral mechanism in which duTRIM14 suppresses TMUV replication by simultaneously promoting proteasomal degradation of NS1 and enhancing the host antiviral response by modulating duTBK1 activity.
坦布苏病毒（TMUV）是一种新出现的禽正黄病毒，在家鸭中可导致产蛋下降综合征和致命性脑炎，造成严重经济损失。为应对这一威胁，宿主免疫系统在控制和消除TMUV感染方面发挥着关键作用。因此，了解这种免疫反应的机制对于制定有效的抗病毒策略至关重要。在本研究中，我们研究了鸭TRIM家族蛋白（duTRIM）对TMUV的抗病毒活性，特别关注duTRIM14作为一种有效的宿主限制因子。我们发现，duTRIM14的过表达显著抑制TMUV复制，而其缺失则导致病毒滴度增加。我们阐明了一种新机制，即duTRIM14与TMUV NS1蛋白相互作用，促进其K27/K29连接的多聚泛素化及随后的蛋白酶体降解。NS1上的Lys141残基被确定为这一过程的关键，去除该残基可显著增强TMUV在体外和体内的复制。此外，我们发现duTRIM14与鸭TBK1（duTBK1）相互作用，促进其在Lys30和Lys401上的K63连接的多聚泛素化，这在很大程度上增强了TMUV感染期间IFN-β的产生。综上所述，这些结果提供了一种新的双作用抗病毒机制，其中duTRIM14通过同时促进NS1的蛋白酶体降解和通过调节duTBK1活性增强宿主抗病毒反应来抑制TMUV复制。
