Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor Regulates Enhanced Activation of Signal Transducer and Activator of Transcription 3 by Epstein-Barr Virus-Derived Epstein-Barr Nuclear Antigen 2

Abstract

The Epstein-Barr virus (EBV)-encoded latency protein Epstein-Barr nuclear antigen 2 (EBNA2) is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. In a previous study, we demonstrated that EBNA2 interacts with signal transducer and activator of transcription 3 (STAT3), a signal transducer for an interleukin (IL)-6 family cytokine, and enhances its transcriptional activity. Here, we show that overexpression of a corepressor, silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), decreases the EBNA2-mediated enhanced STAT3 activation. Furthermore, small-interfering RNA-mediated reduction of endogenous SMRT expression augments the EBNA2-mediated enhanced STAT3 activation. Importantly, EBNA2 reduces interactions between STAT3 and SMRT. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3 by influencing the SMRT corepressor complex.

A Central Role for STAT3 in Gammaherpesvirus-Life Cycle and -Diseases

“…EBV EBNA2 and cellular EGFR have been shown to independently bind STAT3 and increase its transcriptional activity in epithelial cells (Lo et al, 2005 ; Muromoto et al, 2009 ). Interestingly, cellular SMRT (a transcriptional corepressor that facilitates recruitment of histone deacetylases to promoters) was shown to impair EBNA2-mediated STAT3 coactivation while EBNA2 interfered with SMRT and STAT3 interaction in EBV-negative epithelial cells (Ikeda et al, 2009 ). In the context of KSHV, LANA was shown to bind and cause transcriptional coactivation of STAT3 in PEL cells (Figure 3 ); similarly, ORF50 bound to and increased STAT3 transcriptional activity in epithelial cells and fibroblasts (Gwack et al, 2002 ; Muromoto et al, 2006 ).…”

Orbital inflammatory disorders: new knowledge, future challenges

“…Retinoids that accumulate in orbital tissues outside the eye will be henceforth referred to as 'tissue retinoids.' The mechanism of action by retinoids involves the role of retinoids as regulators of transcription through binding to retinoic acid receptors (RAR) and retinoid X receptor (RXR) [34][35][36][37][38][39][40]. These receptors belong to the subfamily of nuclear receptors that also includes thyroid receptor and vitamin D receptor (VDR).…”

“…Indeed, it has long been known that orbital fat is enriched in retinoids [33], and Unsworth et al [26 ▪▪ ] take it a step further by demonstrating that retinoids can diffuse across the sclera in an in-vitro model. Retinoids that accumulate in orbital tissues outside the eye will be henceforth referred to as ‘tissue retinoids.’ The mechanism of action by retinoids involves the role of retinoids as regulators of transcription through binding to retinoic acid receptors (RAR) and retinoid X receptor (RXR) [34–40]. These receptors belong to the subfamily of nuclear receptors that also includes thyroid receptor and vitamin D receptor (VDR).…”