Prohibitin-1 Contributes to Cell-to-Cell Transmission of Herpes Simplex Virus 1 via the MAPK/ERK Signaling Pathway
Prohibitin-1 Contributes to Cell-to-Cell Transmission of Herpes Simplex Virus 1 via the MAPK/ERK Signaling Pathway
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DOI：
10.1128/jvi.01413-20
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发表时间：
2021-02-01
影响因子：
5.4
通讯作者：
Kawaguchi, Yasushi
中科院分区：
文献类型：
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作者：
Watanabe, Mizuki;Arii, Jun;Kawaguchi, Yasushi
病毒细胞间传播是几种病毒家族通过细胞连接进入的一种方法，与各种病毒感染的发病机制高度相关。已知单纯疱疹病毒1（HSV-1）的细胞间传播在很大程度上依赖于包膜糖蛋白E（gE）。然而，gE在HSV-1细胞间传播中起作用的分子机制和其他疱疹病毒细胞间传播的机制仍然知之甚少。在这里，我们描述了我们的识别prohibitin-1作为一种新的gE相互作用的宿主细胞蛋白。异位表达的抑制素-1增加gE依赖的HSV-1细胞间传播。正如在gE无效突变中所观察到的，抑制素-1的表达降低或药理学抑制降低了HSV-1细胞间的扩散，而不影响病毒子代的产量。通过药理学抑制丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）途径产生类似的作用，其中抑制素-1充当蛋白质支架并且是诱导该途径所需的。此外，MAPK/ERK途径的人工激活恢复了由gE无效突变损害的HSV-1细胞间传播。值得注意的是，药理学抑制阿比汀或MAPK/ERK途径减少了所有疱疹病毒亚科中代表性成员的病毒细胞间传播。我们的研究结果表明，prohibitin-1有助于通过MAPK/ERK途径的gE依赖的HSV-1细胞到细胞的传播，这种机制是保守的整个疱疹病毒科，而gE是保守的只有在α疱疹病毒亚科。重要疱疹病毒是各种动物，包括人类普遍存在的病原体。这些病毒主要通过细胞连接传播到未感染的细胞。这种细胞间传播的方法是这些病毒的一个重要致病特征。在这里，我们表明，宿主细胞蛋白prohibitin-1有助于HSV-1通过下游细胞内信号级联，MAPK/ERK途径的细胞间传播。我们还表明，在病毒细胞间传播中，抑制素-1介导的MAPK/ERK通路的作用在每个疱疹病毒亚科的代表性成员中是保守的。这项研究揭示了疱疹病毒细胞间传播的共同分子机制。
Viral cell-to-cell spread, a method employed by several viral families for entrance via cell junctions, is highly relevant to the pathogenesis of various viral infections. Cell-to-cell spread of herpes simplex virus 1 (HSV-1) is known to depend greatly on envelope glycoprotein E (gE). However, the molecular mechanism by which gE acts in HSV-1 cell-to-cell spread and the mechanisms of cell-to-cell spread by other herpesviruses remain poorly understood. Here, we describe our identification of prohibitin-1 as a novel gE-interacting host cell protein. Ectopic expression of prohibitin-1 increased gE-dependent HSV-1 cell-to-cell spread. As observed with the gE-null mutation, decreased expression or pharmacological inhibition of prohibitin-1 reduced HSV-1 cell-to-cell spread without affecting the yield of virus progeny. Similar effects were produced by pharmacological inhibition of the mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, wherein prohibitin-1 acts as a protein scaffold and is required for induction of this pathway. Furthermore, artificial activation of the MAPK/ERK pathway restored HSV-1 cell-to-cell spread impaired by the gE-null mutation. Notably, pharmacological inhibition of prohibitins or the MAPK/ERK pathway reduced viral cell-to-cell spread of representative members in all herpesvirus subfamilies. Our results suggest that prohibitin-1 contributes to gE-dependent HSV-1 cell-to-cell spread via the MAPK/ERK pathway and that this mechanism is conserved throughout the Herpesviridae, whereas gE is conserved only in the Alphaherpesvirinae subfamily.IMPORTANCE Herpesviruses are ubiquitous pathogens of various animals, including humans. These viruses primarily pass through cell junctions to spread to uninfected cells. This method of cell-to-cell spread is an important pathogenic characteristic of these viruses. Here, we show that the host cell protein prohibitin-1 contributes to HSV-1 cell-to-cell spread via a downstream intracellular signaling cascade, the MAPK/ERK pathway. We also demonstrate that the role of the prohibitin-1-mediated MAPK/ERK pathway in viral cell-to-cell spread is conserved in representative members of every herpesvirus subfamily. This study has revealed a common molecular mechanism of the cell-to-cell spread of herpesviruses.