Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry

ABSTRACT Herpes simplex viruses (HSVs) cause significant morbidity and mortality in humans worldwide. Herpesviruses mediate entry by a multicomponent virus-encoded machinery. Herpesviruses enter cells by endosomal low-pH and pH-neutral mechanisms in a cell-specific manner. HSV mediates cell entry vi...

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Autores principales:	Tri Komala Sari, Katrina A. Gianopulos, Darin J. Weed, Seth M. Schneider, Suzanne M. Pritchard, Anthony V. Nicola
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	herpesviruses herpes simplex virus viral entry viral glycoproteins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/106fc3ec4ff3483b94f755349a82042b
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spelling	oai:doaj.org-article:106fc3ec4ff3483b94f755349a82042b2021-11-15T15:27:53ZHerpes Simplex Virus Glycoprotein C Regulates Low-pH Entry10.1128/mSphere.00826-192379-5042https://doaj.org/article/106fc3ec4ff3483b94f755349a82042b2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00826-19https://doaj.org/toc/2379-5042ABSTRACT Herpes simplex viruses (HSVs) cause significant morbidity and mortality in humans worldwide. Herpesviruses mediate entry by a multicomponent virus-encoded machinery. Herpesviruses enter cells by endosomal low-pH and pH-neutral mechanisms in a cell-specific manner. HSV mediates cell entry via the envelope glycoproteins gB and gD and the heterodimer gH/gL regardless of pH or endocytosis requirements. Specifics concerning HSV envelope proteins that function selectively in a given entry pathway have been elusive. Here, we demonstrate that gC regulates cell entry and infection by a low-pH pathway. Conformational changes in the core herpesviral fusogen gB are critical for membrane fusion. The presence of gC conferred a higher pH threshold for acid-induced antigenic changes in gB. Thus, gC may selectively facilitate low-pH entry by regulating conformational changes in the fusion protein gB. We propose that gC modulates the HSV fusion machinery during entry into pathophysiologically relevant cells, such as human epidermal keratinocytes. IMPORTANCE Herpesviruses are ubiquitous pathogens that cause lifelong latent infections and that are characterized by multiple entry pathways. We propose that herpes simplex virus (HSV) gC plays a selective role in modulating HSV entry, such as entry into epithelial cells, by a low-pH pathway. gC facilitates a conformational change of the main fusogen gB, a class III fusion protein. We propose a model whereby gC functions with gB, gD, and gH/gL to allow low-pH entry. In the absence of gC, HSV entry occurs at a lower pH, coincident with trafficking to a lower pH compartment where gB changes occur at more acidic pHs. This report identifies a new function for gC and provides novel insight into the complex mechanism of HSV entry and fusion.Tri Komala SariKatrina A. GianopulosDarin J. WeedSeth M. SchneiderSuzanne M. PritchardAnthony V. NicolaAmerican Society for Microbiologyarticleherpesvirusesherpes simplex virusviral entryviral glycoproteinsMicrobiologyQR1-502ENmSphere, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	herpesviruses herpes simplex virus viral entry viral glycoproteins Microbiology QR1-502
spellingShingle	herpesviruses herpes simplex virus viral entry viral glycoproteins Microbiology QR1-502 Tri Komala Sari Katrina A. Gianopulos Darin J. Weed Seth M. Schneider Suzanne M. Pritchard Anthony V. Nicola Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
description	ABSTRACT Herpes simplex viruses (HSVs) cause significant morbidity and mortality in humans worldwide. Herpesviruses mediate entry by a multicomponent virus-encoded machinery. Herpesviruses enter cells by endosomal low-pH and pH-neutral mechanisms in a cell-specific manner. HSV mediates cell entry via the envelope glycoproteins gB and gD and the heterodimer gH/gL regardless of pH or endocytosis requirements. Specifics concerning HSV envelope proteins that function selectively in a given entry pathway have been elusive. Here, we demonstrate that gC regulates cell entry and infection by a low-pH pathway. Conformational changes in the core herpesviral fusogen gB are critical for membrane fusion. The presence of gC conferred a higher pH threshold for acid-induced antigenic changes in gB. Thus, gC may selectively facilitate low-pH entry by regulating conformational changes in the fusion protein gB. We propose that gC modulates the HSV fusion machinery during entry into pathophysiologically relevant cells, such as human epidermal keratinocytes. IMPORTANCE Herpesviruses are ubiquitous pathogens that cause lifelong latent infections and that are characterized by multiple entry pathways. We propose that herpes simplex virus (HSV) gC plays a selective role in modulating HSV entry, such as entry into epithelial cells, by a low-pH pathway. gC facilitates a conformational change of the main fusogen gB, a class III fusion protein. We propose a model whereby gC functions with gB, gD, and gH/gL to allow low-pH entry. In the absence of gC, HSV entry occurs at a lower pH, coincident with trafficking to a lower pH compartment where gB changes occur at more acidic pHs. This report identifies a new function for gC and provides novel insight into the complex mechanism of HSV entry and fusion.
format	article
author	Tri Komala Sari Katrina A. Gianopulos Darin J. Weed Seth M. Schneider Suzanne M. Pritchard Anthony V. Nicola
author_facet	Tri Komala Sari Katrina A. Gianopulos Darin J. Weed Seth M. Schneider Suzanne M. Pritchard Anthony V. Nicola
author_sort	Tri Komala Sari
title	Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
title_short	Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
title_full	Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
title_fullStr	Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
title_full_unstemmed	Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry
title_sort	herpes simplex virus glycoprotein c regulates low-ph entry
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/106fc3ec4ff3483b94f755349a82042b
work_keys_str_mv	AT trikomalasari herpessimplexvirusglycoproteincregulateslowphentry AT katrinaagianopulos herpessimplexvirusglycoproteincregulateslowphentry AT darinjweed herpessimplexvirusglycoproteincregulateslowphentry AT sethmschneider herpessimplexvirusglycoproteincregulateslowphentry AT suzannempritchard herpessimplexvirusglycoproteincregulateslowphentry AT anthonyvnicola herpessimplexvirusglycoproteincregulateslowphentry
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Herpes Simplex Virus Glycoprotein C Regulates Low-pH Entry

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