Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi’s sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells...

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Autores principales:	Jia Chen, Xianming Zhang, Samantha Schaller, Theodore S. Jardetzky, Richard Longnecker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Eph receptors EphA4 Kaposi’s sarcoma-associated herpesvirus viral entry gH/gL Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e46b692338bd4cd4a009ca9fb5a90916
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spelling	oai:doaj.org-article:e46b692338bd4cd4a009ca9fb5a909162021-11-15T15:55:13ZEphrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor10.1128/mBio.02892-182150-7511https://doaj.org/article/e46b692338bd4cd4a009ca9fb5a909162019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02892-18https://doaj.org/toc/2150-7511ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi’s sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular receptors. In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA sequencing (RNA-seq) data analysis of existing data sets. We found that these cell types broadly express both EphA2 and EphA4, with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single- and double-knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells. Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both Epstein-Barr virus (EBV) and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry receptor for KSHV. IMPORTANCE The overall entry mechanism for herpesviruses is not completely known, including those for the human gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional receptors need to be identified. In the current study, we found that EphA4 can also function for a KSHV entry receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry receptor for EBV, whereas EphA2 does. The discovery of EphA4 as a KSHV entry receptor has important implications for KSHV pathogenesis in humans, may prove useful in understanding the unique pathogenesis of KSHV infection in humans, and may uncover new potential targets that can be used for the development of novel interventional strategies.Jia ChenXianming ZhangSamantha SchallerTheodore S. JardetzkyRichard LongneckerAmerican Society for MicrobiologyarticleEph receptorsEphA4Kaposi’s sarcoma-associated herpesvirusviral entrygH/gLMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Eph receptors EphA4 Kaposi’s sarcoma-associated herpesvirus viral entry gH/gL Microbiology QR1-502
spellingShingle	Eph receptors EphA4 Kaposi’s sarcoma-associated herpesvirus viral entry gH/gL Microbiology QR1-502 Jia Chen Xianming Zhang Samantha Schaller Theodore S. Jardetzky Richard Longnecker Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
description	ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi’s sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular receptors. In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA sequencing (RNA-seq) data analysis of existing data sets. We found that these cell types broadly express both EphA2 and EphA4, with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single- and double-knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells. Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both Epstein-Barr virus (EBV) and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry receptor for KSHV. IMPORTANCE The overall entry mechanism for herpesviruses is not completely known, including those for the human gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional receptors need to be identified. In the current study, we found that EphA4 can also function for a KSHV entry receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry receptor for EBV, whereas EphA2 does. The discovery of EphA4 as a KSHV entry receptor has important implications for KSHV pathogenesis in humans, may prove useful in understanding the unique pathogenesis of KSHV infection in humans, and may uncover new potential targets that can be used for the development of novel interventional strategies.
format	article
author	Jia Chen Xianming Zhang Samantha Schaller Theodore S. Jardetzky Richard Longnecker
author_facet	Jia Chen Xianming Zhang Samantha Schaller Theodore S. Jardetzky Richard Longnecker
author_sort	Jia Chen
title	Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
title_short	Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
title_full	Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
title_fullStr	Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
title_full_unstemmed	Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
title_sort	ephrin receptor a4 is a new kaposi’s sarcoma-associated herpesvirus virus entry receptor
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e46b692338bd4cd4a009ca9fb5a90916
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Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor

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