Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly
Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly
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Hsp90 抑制剂 AT-533 阻断 HSV-1 核排出和组装
DOI：
10.1093/jb/mvy066
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发表时间：
2018-12-01
影响因子：
2.7
通讯作者：
Wang, Yifei
中科院分区：
文献类型：
--
作者：
Li, Feng;Jin, Fujun;Wang, Yifei
热休克蛋白90（Hsp 90）已被确定为包括HSV-1在内的几种病毒感染和复制的重要宿主因子。最近的工作清楚地表明，Hsp 90在HSV-1感染的早期阶段发挥作用，包括核输入和DNA复制。然而，Hsp 90在HSV-1感染晚期的作用仍不清楚。在这项研究中，我们发现Hsp 90在病毒感染晚期上调。用Hsp 90抑制剂AT-533处理显著降低细胞内和细胞外病毒滴度，并强烈抑制核衣壳从细胞核排出。更详细的研究表明，AT-533通过抑制核相关蛋白pUL 31和pUL 34的表达和易位来抑制病毒核衣壳的核出口。此外，我们还发现AT-533可能通过影响糖蛋白在内质网和高尔基体中的定位而阻碍病毒颗粒的组装。这些结果提示Hsp 90在HSV-1的核衣壳排出和病毒成熟中具有新的作用，并进一步促进Hsp 90抑制剂作为潜在的抗HSV-1药物的开发。
Heat shock protein 90 (Hsp90) has been identified as an essential host factor for the infection and replication of several viruses, including HSV-1. Recent works have clearly shown that Hsp90 plays a role in the early stages of HSV-1 infection, including nuclear import and DNA replication. However, the role of Hsp90 in the late stages of HSV-1 infection remains unclear. In this study, we found that Hsp90 was up-regulated during late viral infection. Treatment with the Hsp90 inhibitor AT-533 significantly decreased the intracellular and extracellular virus titers, and strongly inhibited nucleocapsid egress from the nucleus. More detailed studies revealed that AT-533 inhibited the nuclear egress of the viral nucleocapsid by suppressing the expression and translocation of nuclear-associated proteins pUL31 and pUL34. In addition, we found that AT-533 hindered the assembly of virus particles possibly though affecting the localization of glycoproteins in the endoplasmic reticulum and Golgi apparatus. These results thus invoke a new role for Hsp90 in the nucleocapsid egress and viral maturation of HSV-1, and further promote the development of Hsp90 inhibitors as potential anti-HSV-1 drugs.