Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation

ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that persistently infects humans, with nearly 95% seropositivity in adults. Infection in differentiating epithelia is permissive, but EBV-associated nasopharyngeal carcinoma (NPC) tumors harbor a clonal and nonproductive latent infec...

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Autores principales:	Elizabeth A. Caves, Rachel M. Butch, Sarah A. Cook, Laura R. Wasil, Chen Chen, Yuanpu Peter Di, Nara Lee, Kathy H. Y. Shair
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Epstein-Barr virus gammaherpesvirus pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ead35caec1924fa593e364da3b73822f
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spelling	oai:doaj.org-article:ead35caec1924fa593e364da3b73822f2021-11-15T15:21:52ZLatent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation10.1128/mSphereDirect.00453-172379-5042https://doaj.org/article/ead35caec1924fa593e364da3b73822f2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphereDirect.00453-17https://doaj.org/toc/2379-5042ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that persistently infects humans, with nearly 95% seropositivity in adults. Infection in differentiating epithelia is permissive, but EBV-associated nasopharyngeal carcinoma (NPC) tumors harbor a clonal and nonproductive latent infection. However, in explanted NPC cultures and epithelial cell lines, episomal EBV genomes are frequently lost. The resulting unstable infection has hampered efforts to study the determinants of EBV persistence and latency in epithelial oncogenesis. The EBV nuclear antigen 1 (EBNA1) protein is required for tethering EBV episomes to cellular DNA and for mitotic segregation to daughter cells. Expression of EBNA1 does not ensure faithful partitioning of EBV episomes or replicons, suggesting that additional regulatory mechanisms have yet to be elucidated. The EBV latent membrane protein 1 (LMP1) is an oncogenic signaling protein expressed in latent and lytic cycles. This study identified that LMP1 contributes to the loss of EBV genomes in latently infected cells and promotes differentiation-induced lytic replication in a polarized air-liquid interface (ALI) culture model. Deletion of LMP1 in recombinantly infected 293 cells promoted the retention of EBV genomes in passaged cells, which was in part localized to a conserved PXQXT motif in the C-terminal signaling domain (CTAR1). Additionally, knockdown of LMP1 in the recombinantly infected NPC cell line HK1 resulted in decreased induction of lytic proteins and infectious EBV titers. These findings are consistent with the hypothesis that in epithelial infections, regulation of LMP1 mechanisms may be a determinant of infection outcome and a potential risk factor for EBV persistence in preneoplastic cells. IMPORTANCE Latent membrane protein 1 (LMP1) is a constitutively active oncogenic signaling protein encoded by Epstein-Barr virus (EBV). Despite monoclonal infection in cases of nasopharyngeal carcinoma (NPC), it has been difficult to reconcile the heterogeneous LMP1 protein levels detected in tumor cells. The LMP1 protein is a pleiotropic signaling protein with oncogenic potential. Findings from this study are consistent with the hypothesis that LMP1 has a role distinct from that of oncogenesis that facilitates the viral life cycle by promoting an unstable but productive infection in differentiating epithelia.Elizabeth A. CavesRachel M. ButchSarah A. CookLaura R. WasilChen ChenYuanpu Peter DiNara LeeKathy H. Y. ShairAmerican Society for MicrobiologyarticleEpstein-Barr virusgammaherpesviruspathogenesisMicrobiologyQR1-502ENmSphere, Vol 2, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Epstein-Barr virus gammaherpesvirus pathogenesis Microbiology QR1-502
spellingShingle	Epstein-Barr virus gammaherpesvirus pathogenesis Microbiology QR1-502 Elizabeth A. Caves Rachel M. Butch Sarah A. Cook Laura R. Wasil Chen Chen Yuanpu Peter Di Nara Lee Kathy H. Y. Shair Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
description	ABSTRACT Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that persistently infects humans, with nearly 95% seropositivity in adults. Infection in differentiating epithelia is permissive, but EBV-associated nasopharyngeal carcinoma (NPC) tumors harbor a clonal and nonproductive latent infection. However, in explanted NPC cultures and epithelial cell lines, episomal EBV genomes are frequently lost. The resulting unstable infection has hampered efforts to study the determinants of EBV persistence and latency in epithelial oncogenesis. The EBV nuclear antigen 1 (EBNA1) protein is required for tethering EBV episomes to cellular DNA and for mitotic segregation to daughter cells. Expression of EBNA1 does not ensure faithful partitioning of EBV episomes or replicons, suggesting that additional regulatory mechanisms have yet to be elucidated. The EBV latent membrane protein 1 (LMP1) is an oncogenic signaling protein expressed in latent and lytic cycles. This study identified that LMP1 contributes to the loss of EBV genomes in latently infected cells and promotes differentiation-induced lytic replication in a polarized air-liquid interface (ALI) culture model. Deletion of LMP1 in recombinantly infected 293 cells promoted the retention of EBV genomes in passaged cells, which was in part localized to a conserved PXQXT motif in the C-terminal signaling domain (CTAR1). Additionally, knockdown of LMP1 in the recombinantly infected NPC cell line HK1 resulted in decreased induction of lytic proteins and infectious EBV titers. These findings are consistent with the hypothesis that in epithelial infections, regulation of LMP1 mechanisms may be a determinant of infection outcome and a potential risk factor for EBV persistence in preneoplastic cells. IMPORTANCE Latent membrane protein 1 (LMP1) is a constitutively active oncogenic signaling protein encoded by Epstein-Barr virus (EBV). Despite monoclonal infection in cases of nasopharyngeal carcinoma (NPC), it has been difficult to reconcile the heterogeneous LMP1 protein levels detected in tumor cells. The LMP1 protein is a pleiotropic signaling protein with oncogenic potential. Findings from this study are consistent with the hypothesis that LMP1 has a role distinct from that of oncogenesis that facilitates the viral life cycle by promoting an unstable but productive infection in differentiating epithelia.
format	article
author	Elizabeth A. Caves Rachel M. Butch Sarah A. Cook Laura R. Wasil Chen Chen Yuanpu Peter Di Nara Lee Kathy H. Y. Shair
author_facet	Elizabeth A. Caves Rachel M. Butch Sarah A. Cook Laura R. Wasil Chen Chen Yuanpu Peter Di Nara Lee Kathy H. Y. Shair
author_sort	Elizabeth A. Caves
title	Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
title_short	Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
title_full	Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
title_fullStr	Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
title_full_unstemmed	Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation
title_sort	latent membrane protein 1 is a novel determinant of epstein-barr virus genome persistence and reactivation
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/ead35caec1924fa593e364da3b73822f
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Latent Membrane Protein 1 Is a Novel Determinant of Epstein-Barr Virus Genome Persistence and Reactivation

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