Prohibitin-1 Contributes to Cell-to-Cell Transmission of Herpes Simplex Virus 1 via the MAPK/ERK Signaling Pathway.

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE

Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.

Cell Communication*; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Herpes Simplex/*virology ; Herpesvirus 1, Human/*physiology ; Mitogen-Activated Protein Kinases/*metabolism ; Repressor Proteins/*metabolism ; Viral Envelope Proteins/*metabolism; A549 Cells ; Extracellular Signal-Regulated MAP Kinases/genetics ; Herpes Simplex/genetics ; Herpes Simplex/metabolism ; Humans ; Intercellular Junctions ; Mitogen-Activated Protein Kinases/genetics ; Prohibitins ; Repressor Proteins/genetics ; Viral Envelope Proteins/genetics ; Virus Replication

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 mitogen-activated 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.
(Copyright © 2021 American Society for Microbiology.)

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Keywords: cell-to-cell spread; glycoproteins; herpes simplex virus

0 (Prohibitins)
0 (Repressor Proteins)
0 (Viral Envelope Proteins)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)

Date Created: 20201112 Date Completed: 20210315 Latest Revision: 20211204

20221213

PMC7925112

10.1128/JVI.01413-20

33177205