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Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes.
J Virol. 2015 May; 89(9):5002-11.JV

Abstract

A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle-promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV(+)) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV(+) cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV-associated cancers.

IMPORTANCE

Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV(+) cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies.

Authors+Show Affiliations

Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA.Bioinformatics Core Facility, Stony Brook University School of Medicine, Stony Brook, New York, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA.Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA.Graduate Program in Genetics, Stony Brook University School of Medicine, Stony Brook, New York, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA.Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York, USA Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA sumita.bhaduri-mcintosh@stonybrookmedicine.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25717101

Citation

Koganti, Siva, et al. "Cellular STAT3 Functions Via PCBP2 to Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes." Journal of Virology, vol. 89, no. 9, 2015, pp. 5002-11.
Koganti S, Clark C, Zhi J, et al. Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes. J Virol. 2015;89(9):5002-11.
Koganti, S., Clark, C., Zhi, J., Li, X., Chen, E. I., Chakrabortty, S., Hill, E. R., & Bhaduri-McIntosh, S. (2015). Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes. Journal of Virology, 89(9), 5002-11. https://doi.org/10.1128/JVI.00121-15
Koganti S, et al. Cellular STAT3 Functions Via PCBP2 to Restrain Epstein-Barr Virus Lytic Activation in B Lymphocytes. J Virol. 2015;89(9):5002-11. PubMed PMID: 25717101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes. AU - Koganti,Siva, AU - Clark,Carissa, AU - Zhi,Jizu, AU - Li,Xiaofan, AU - Chen,Emily I, AU - Chakrabortty,Sharmistha, AU - Hill,Erik R, AU - Bhaduri-McIntosh,Sumita, Y1 - 2015/02/25/ PY - 2015/01/16/received PY - 2015/02/13/accepted PY - 2015/2/27/entrez PY - 2015/2/27/pubmed PY - 2015/6/11/medline SP - 5002 EP - 11 JF - Journal of virology JO - J Virol VL - 89 IS - 9 N2 - UNLABELLED: A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle-promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV(+)) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV(+) cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV-associated cancers. IMPORTANCE: Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV(+) cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/25717101/Cellular_STAT3_functions_via_PCBP2_to_restrain_Epstein_Barr_Virus_lytic_activation_in_B_lymphocytes_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=25717101 DB - PRIME DP - Unbound Medicine ER -