Epstein-Barr virus utilizes ikaros in regulating its latent-lytic switch in B cells

Tawin Iempridee, Jessica A. Reusch, Andrew Riching, Eric C. Johannsen, Sinisa Dovat, Shannon C. Kenney, Janet E. Mertz

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Ikaros is a zinc finger DNA-binding protein that regulates chromatin remodeling and the expression of genes involved in the cell cycle, apoptosis, and Notch signaling. It is a master regulator of lymphocyte differentiation and functions as a tumor suppressor in acute lymphoblastic leukemia. Nevertheless, no previous reports described effects of Ikaros on the life cycle of any human lymphotropic virus. Here, we demonstrate that full-length Ikaros (IK-1) functions as a major factor in the maintenance of viral latency in Epstein-Barr virus (EBV)-positive Burkitt's lymphoma Sal and MutuI cell lines. Either silencing of Ikaros expression by small hairpin RNA (shRNA) knockdown or ectopic expression of a non-DNA-binding isoform induced lytic gene expression. These effects synergized with other lytic inducers of EBV, including transforming growth factor β (TGF-β) and the hypoxia mimic desferrioxamine. Data from chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) and ChIP-sequencing (ChIP-seq) analyses indicated that Ikaros did not bind to either of the EBV immediate early genes BZLF1 and BRLF1. Rather, Ikaros affected the expression of Oct-2 and Bcl-6, other transcription factors that directly inhibit EBV reactivation and plasma cell differentiation, respectively. IK-1 also complexed with the EBV immediate early R protein in coimmunoprecipitation assays and partially colocalized with R within cells. The presence of R alleviated IK-1-mediated transcriptional repression, with IK-1 then cooperating with Z and R to enhance lytic gene expression. Thus, we conclude that Ikaros plays distinct roles at different stages of EBV's life cycle: it contributes to maintaining latency via indirect mechanisms, and it may also synergize with Z and R to enhance lytic replication through direct association with R and/or R-induced alterations in Ikaros' functional activities via cellular signaling pathways.

Original languageEnglish (US)
Pages (from-to)4811-4827
Number of pages17
JournalJournal of virology
Volume88
Issue number9
DOIs
StatePublished - May 2014

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Iempridee, T., Reusch, J. A., Riching, A., Johannsen, E. C., Dovat, S., Kenney, S. C., & Mertz, J. E. (2014). Epstein-Barr virus utilizes ikaros in regulating its latent-lytic switch in B cells. Journal of virology, 88(9), 4811-4827. https://doi.org/10.1128/JVI.03706-13