Hsp90 Inhibitors Inhibit the Entry of Herpes Simplex Virus 1 Into Neuron Cells by Regulating Cofilin-Mediated F-Actin Reorganization.
Hsp90 Inhibitors Inhibit the Entry of Herpes Simplex Virus 1 Into Neuron Cells by Regulating Cofilin-Mediated F-Actin Reorganization.
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Hsp90 抑制剂通过调节 Cofilin 介导的 F-肌动蛋白重组来抑制单纯疱疹病毒 1 进入神经元细胞
DOI：
10.3389/fmicb.2021.799890
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发表时间：
2021
影响因子：
5.2
通讯作者：
Ren Z
中科院分区：
文献类型：
--
作者：
Song X;Wang Y;Li F;Cao W;Zeng Q;Qin S;Wang Z;Jia J;Xiao J;Hu X;Liu K;Wang Y;Ren Z
单纯疱疹病毒1型（HSV-1）是一种常见的嗜神经病毒，由其引起的单纯疱疹脑炎（HSE）被认为是最常见的散发性但致命的脑炎。针对 HSV-1 的传统抗病毒药物仅限于针对病毒因子的核苷类似物。热休克蛋白 90 (Hsp90) 的抑制通过多种机制具有有效的抗 HSV-1 活性，但 Hsp90 抑制剂对神经元细胞中 HSV-1 感染的影响，特别是在病毒进入阶段，仍不清楚。在本研究中，我们旨在研究 Hsp90 抑制剂对 HSV-1 神经元细胞感染的影响。有趣的是，我们发现Hsp90抑制剂促进病毒吸附，但抑制随后在神经元细胞系和原代神经元中的渗透，这共同赋予了Hsp90抑制剂的抗病毒活性。从机械角度来看，Hsp90抑制剂主要损害Hsp90与丝切蛋白之间的相互作用，导致丝切蛋白膜分布减少，从而导致F-肌动蛋白聚合以促进病毒附着。然而，F-肌动蛋白的过度聚合抑制了随后的病毒渗透。因此，单向 F-肌动蛋白聚合限制了 HSV-1 病毒粒子进入神经元细胞。我们的研究拓展了Hsp90在神经元细胞HSV-1感染中的分子机制，为开发针对Hsp90的抗病毒药物提供了理论基础。
Herpes simplex virus 1 (HSV-1) is a common neurotropic virus, the herpes simplex encephalitis (HSE) caused by which is considered to be the most common sporadic but fatal encephalitis. Traditional antiviral drugs against HSV-1 are limited to nucleoside analogs targeting viral factors. Inhibition of heat shock protein 90 (Hsp90) has potent anti-HSV-1 activities via numerous mechanisms, but the effects of Hsp90 inhibitors on HSV-1 infection in neuronal cells, especially in the phase of virus entry, are still unknown. In this study, we aimed to investigate the effects of the Hsp90 inhibitors on HSV-1 infection of neuronal cells. Interestingly, we found that Hsp90 inhibitors promoted viral adsorption but inhibited subsequent penetration in neuronal cell lines and primary neurons, which jointly confers the antiviral activity of the Hsp90 inhibitors. Mechanically, Hsp90 inhibitors mainly impaired the interaction between Hsp90 and cofilin, resulting in reduced cofilin membrane distribution, which led to F-actin polymerization to promote viral attachment. However, excessive polymerization of F-actin inhibited subsequent viral penetration. Consequently, unidirectional F-actin polymerization limits the entry of HSV-1 virions into neuron cells. Our research extended the molecular mechanism of Hsp90 in HSV-1 infection in neuron cells and provided a theoretical basis for developing antiviral drugs targeting Hsp90.
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