title: Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells.
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.
  
  
  OBJECTIVE
  This is the first report showing that the cellular protein Ikaros, a known master regulator of hematopoiesis and critical tumor suppressor in acute lymphoblastic leukemia, also plays important roles in the life cycle of Epstein-Barr virus in B cells.
authors: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors: Tawin
authors: T
authors: Iempridee
authors: Jessica A
authors: JA
authors: Reusch
authors: Andrew
authors: A
authors: Riching
authors: Eric C
authors: EC
authors: Johannsen
authors: Sinisa
authors: S
authors: Dovat
authors: Shannon C
authors: SC
authors: Kenney
authors: Janet E
authors: JE
authors: Mertz
mesh_terms: D001402:B-Lymphocytes / Q000821:virology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D004854:Herpesvirus 4, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D011485:Protein Binding; D017735:Virus Latency
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor