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Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus.
J Virol. 2020 03 17; 94(7)JV

Abstract

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.IMPORTANCE Transition from latency to the lytic phase is necessary for herpesvirus-mediated pathology as well as viral spread and persistence in the population at large. Yet, viral genomes in only some cells in a population of latently infected cells respond to lytic triggers, resulting in subpopulations of responsive/lytic and refractory cells. Our investigations into this partially permissive phenotype of the herpesvirus Epstein-Barr virus (EBV) indicate that upon exposure to lytic triggers, certain cellular genes are transcriptionally upregulated, while viral latency genes are downregulated ahead of expression of the viral latent-to-lytic switch protein. These cellular genes contribute to lytic susceptibility to various degrees. Apart from indicating that there may be a cellular "prolytic" state, our findings indicate that (i) early transcriptional upregulation of cellular genes counters the well-known viral-nuclease-mediated host shutoff and (ii) subsequent transcriptional downregulation of a subset of early upregulated cellular genes is a previously undescribed mode of host shutoff.

Authors+Show Affiliations

Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University, New York, USA.Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University, New York, USA.Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.Department of Radiation Oncology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA. Center for RNA Biomedicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.Department of Radiation Oncology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA. Center for RNA Biomedicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, Florida, USA mmcintosh@peds.ufl.edu sbhadurimcintosh@ufl.edu. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA mmcintosh@peds.ufl.edu sbhadurimcintosh@ufl.edu. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31941784

Citation

Frey, Tiffany R., et al. "Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus." Journal of Virology, vol. 94, no. 7, 2020.
Frey TR, Brathwaite J, Li X, et al. Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus. J Virol. 2020;94(7).
Frey, T. R., Brathwaite, J., Li, X., Burgula, S., Akinyemi, I. A., Agarwal, S., Burton, E. M., Ljungman, M., McIntosh, M. T., & Bhaduri-McIntosh, S. (2020). Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus. Journal of Virology, 94(7). https://doi.org/10.1128/JVI.01966-19
Frey TR, et al. Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus. J Virol. 2020 03 17;94(7) PubMed PMID: 31941784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nascent Transcriptomics Reveal Cellular Prolytic Factors Upregulated Upstream of the Latent-to-Lytic Switch Protein of Epstein-Barr Virus. AU - Frey,Tiffany R, AU - Brathwaite,Jozan, AU - Li,Xiaofan, AU - Burgula,Sandeepta, AU - Akinyemi,Ibukun A, AU - Agarwal,Saurabh, AU - Burton,Eric M, AU - Ljungman,Mats, AU - McIntosh,Michael T, AU - Bhaduri-McIntosh,Sumita, Y1 - 2020/03/17/ PY - 2019/11/21/received PY - 2020/01/08/accepted PY - 2020/1/17/pubmed PY - 2020/9/15/medline PY - 2020/1/17/entrez KW - Bru-Seq KW - Epstein-Barr virus KW - lytic switch KW - nascent transcriptomics KW - prolytic factors JF - Journal of virology JO - J Virol VL - 94 IS - 7 N2 - 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.IMPORTANCE Transition from latency to the lytic phase is necessary for herpesvirus-mediated pathology as well as viral spread and persistence in the population at large. Yet, viral genomes in only some cells in a population of latently infected cells respond to lytic triggers, resulting in subpopulations of responsive/lytic and refractory cells. Our investigations into this partially permissive phenotype of the herpesvirus Epstein-Barr virus (EBV) indicate that upon exposure to lytic triggers, certain cellular genes are transcriptionally upregulated, while viral latency genes are downregulated ahead of expression of the viral latent-to-lytic switch protein. These cellular genes contribute to lytic susceptibility to various degrees. Apart from indicating that there may be a cellular "prolytic" state, our findings indicate that (i) early transcriptional upregulation of cellular genes counters the well-known viral-nuclease-mediated host shutoff and (ii) subsequent transcriptional downregulation of a subset of early upregulated cellular genes is a previously undescribed mode of host shutoff. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/31941784/Nascent_Transcriptomics_Reveal_Cellular_Prolytic_Factors_Upregulated_Upstream_of_the_Latent_to_Lytic_Switch_Protein_of_Epstein_Barr_Virus_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31941784/ DB - PRIME DP - Unbound Medicine ER -