Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

In order to eliminate viral infections, hundreds of interferon-stimulated genes (ISGs) are induced via type I interferons (IFNs). However, the functions and mechanisms of most ISGs are largely unclear. A tripartite motif (TRIM) protein encoding gene TRIM69 is induced by dengue virus (DENV) infection as an ISG. TRIM69 restricts DENV replication, and its RING domain, which has the E3 ubiquitin ligase activity, is critical for its antiviral activity. An in vivo study further confirmed that TRIM69 contributes to the control of DENV infection in immunocompetent mice. Unlike many other TRIM family members, TRIM69 is not involved in modulation of IFN signaling. Instead, TRIM69 interacts with DENV Nonstructural Protein 3 (NS3) directly and mediates its polyubiquitination and degradation. Finally, Lys104 of NS3 is identified as the target of TRIM69-mediated ubiquitination. Our study demonstrates that TRIM69 restricts DENV replication by specifically ubiquitinating a viral nonstructural protein.

为清除病毒感染，宿主通过I型干扰素（type I interferons, IFNs）诱导表达数百种干扰素刺激基因（interferon-stimulated genes, ISGs）。然而，绝大多数干扰素刺激基因的功能与作用机制仍未得到充分阐明。作为一类干扰素刺激基因，编码三分体基序（tripartite motif, TRIM）蛋白的TRIM69可被登革病毒（dengue virus, DENV）感染诱导表达。TRIM69可抑制登革病毒的复制，其具备E3泛素连接酶活性的RING结构域对于其抗病毒活性至关重要。一项体内研究进一步证实，TRIM69可在免疫健全小鼠体内发挥控制登革病毒感染的作用。与多数其他TRIM家族成员不同，TRIM69并不参与调控干扰素信号通路。相反，TRIM69可直接与登革病毒非结构蛋白3（Nonstructural Protein 3, NS3）相结合，并介导该蛋白发生多聚泛素化修饰与降解。研究人员最终鉴定出NS3的Lys104位点是TRIM69介导的泛素化修饰靶点。本研究证实，TRIM69通过特异性靶向病毒非结构蛋白进行泛素化修饰，从而抑制登革病毒的复制。