Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus.
Apoptosis
Cell Line, Tumor
Gene Expression Profiling
Gene Expression Regulation, Viral
Herpesvirus 4, Human
/ physiology
Host-Pathogen Interactions
/ genetics
Humans
Inflammation
Phenotype
Promoter Regions, Genetic
RNA, Small Interfering
/ metabolism
Trans-Activators
/ genetics
Transcriptional Activation
Transcriptome
Viral Load
Virus Latency
Bru-Seq
Epstein-Barr virus
lytic switch
nascent transcriptomics
prolytic factors
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
17 03 2020
17 03 2020
Historique:
received:
21
11
2019
accepted:
08
01
2020
pubmed:
17
1
2020
medline:
15
9
2020
entrez:
17
1
2020
Statut:
epublish
Résumé
Lytic activation from latency is a key transition point in the life cycle of herpesviruses. Epstein-Barr virus (EBV) is a human herpesvirus that can cause lymphomas, epithelial cancers, and other diseases, most of which require the lytic cycle. While the lytic cycle of EBV can be triggered by chemicals and immunologic ligands, the lytic cascade is activated only when expression of the EBV latent-to-lytic switch protein ZEBRA is turned on. ZEBRA then transcriptionally activates other EBV genes and, together with some of those gene products, ensures completion of the lytic cycle. However, not every latently infected cell exposed to a lytic trigger turns on the expression of ZEBRA, resulting in responsive and refractory subpopulations. What governs this dichotomy? By examining the nascent transcriptome following exposure to a lytic trigger, we find that several cellular genes are transcriptionally upregulated temporally upstream of ZEBRA. These genes regulate lytic susceptibility to various degrees in latently infected cells that respond to mechanistically distinct lytic triggers. While increased expression of these cellular genes defines a prolytic state, such upregulation also runs counter to the well-known mechanism of viral-nuclease-mediated host shutoff that is activated downstream of ZEBRA. Furthermore, a subset of upregulated cellular genes is transcriptionally repressed temporally downstream of ZEBRA, indicating an additional mode of virus-mediated host shutoff through transcriptional repression. Thus, increased transcription of a set of host genes contributes to a prolytic state that allows a subpopulation of cells to support the EBV lytic cycle.
Identifiants
pubmed: 31941784
pii: JVI.01966-19
doi: 10.1128/JVI.01966-19
pmc: PMC7081890
pii:
doi:
Substances chimiques
BZLF1 protein, Herpesvirus 4, Human
0
RNA, Small Interfering
0
Trans-Activators
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI113134
Pays : United States
Organisme : NIAID NIH HHS
ID : R41 AI115834
Pays : United States
Informations de copyright
Copyright © 2020 American Society for Microbiology.
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