Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3.
Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3.
复制标题
干扰素刺激的 TRIM69 通过泛素化病毒非结构蛋白 3 来中断登革热病毒复制。
DOI：
10.1371/journal.ppat.1007287
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发表时间：
2018-08
期刊：
影响因子：
6.7
通讯作者：
Dai J
中科院分区：
文献类型：
--
作者：
Wang K;Zou C;Wang X;Huang C;Feng T;Pan W;Wu Q;Wang P;Dai J
为了消除病毒感染，通过I型干扰素（IFN）诱导数百个干扰素刺激基因（ISG）。然而，大多数国际支助小组的职能和机制在很大程度上并不清楚。TRIM 69基因是由登革病毒（DENV）感染诱导的一种三重基序（TRIM）蛋白。TRIM69限制DENV复制，并且其具有E3泛素连接酶活性的RING结构域对其抗病毒活性至关重要。体内研究进一步证实了TRIM69有助于控制免疫活性小鼠中的DENV感染。与许多其他TRIM家族成员不同，TRIM69不参与IFN信号传导的调节。相反，TRIM69与DENV非结构蛋白3（NS3）直接相互作用并介导其多聚泛素化和降解。最后，NS3的Lys104被鉴定为TRIM69介导的泛素化的靶标。我们的研究表明TRIM69通过特异性泛素化病毒非结构蛋白来限制DENV复制。近年来，登革热病毒（DENV）等蚊媒病毒已成为全球性的人类健康威胁。然而，尚无抗病毒药物被批准用于治疗DENV引起的疾病，安全有效的疫苗仍在开发中。深入研究宿主与病毒相互作用的具体机制具有重要意义。在这份报告中，我们发现，干扰素诱导的宿主蛋白，TRIM69，在DENV感染后上调。TRIM69在体外和体内均作为DENV复制的限制因子。作为E3泛素连接酶，TRIM 69直接与病毒非结构蛋白3（NS3）结合，导致NS3泛素化和降解。因此，TRIM69是一种新的干扰素诱导的宿主抗病毒因子，通过靶向特定的病毒蛋白降解。
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. Mosquito-borne viruses, such as Dengue virus (DENV), have become global threats to human health in recent years. However, no antiviral drugs have been approved to treat DENV induced diseases, and the safe and effective vaccines are still under development. It is of great importance to explore the detail mechanisms of host-virus interaction. In this report, we found that an interferon inducible host protein, TRIM69, is upregulated upon DENV infection. TRIM69 acts as a restriction factor for DENV replication both in vitro and in vivo. As an E3 ubiquitin ligase, TRIM69 directly binds to viral Nonstructural Protein 3 (NS3), which leads to NS3 ubiquitination and degradation. Thus TRIM69 is a novel interferon inducible host antiviral factor by targeting a specific viral protein for its degradation.
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