Regulation of Transactivation Function of the Aryl Hydrocarbon Receptor by the Epstein-Barr Virus-encoded EBNA-3 Protein

Abstract

EBNA-3 is one of the Epstein-Barr virus (EBV)-encoded nuclear antigens that is indispensable for immunoblastic transformationand sustained proliferation of B-lymphocytes. The molecular mechanisms responsible for the function of EBNA-3 are poorly understood. We previously found that EBNA-3 interacts with an immunophilin-like protein XAP2/ARA9/AIP, which in mammalian cells is known to interact with the latent aryl hydrocarbon receptor (AhR). AhR is a ligand-inducible transcription factor that mediates cellular responses to environmental pollutants, such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). In this study, we show that EBNA-3 interacts specifically with AhR. The stability of this interaction is determined by the activation state of AhR and its association with XAP2. We and others have demonstrated that XAP2 retains the nonactivated AhR in the cell cytoplasm. However, in the presence of TCDD, the effect of XAP2 on the intracellular localization of AhR was counter-acted by EBNA-3, resulting in nuclear translocation of the AhR. In addition, EBNA-3 enhanced transactivation function by the ligand-activated AhR in cells, as assessed by reporter gene assays. Our data suggested that EBNA-3 plays a role in facilitating the ligand-dependent AhR activation process. Following activation of the AhR, we also observed that EBNA-3 counteracted the inhibitory effect of TCDD on the growth of EBV-carrying lymphoblasts. Taken together, our studies revealed a novel interaction between EBV-and AhR-dependent cellular pathways that control cell proliferation and survival.

Aryl Hydrocarbon Receptor-Mediated Induction of EBV Reactivation as a Risk Factor for Sjögren’s Syndrome

“…The overexpression of EBNA-3 induces G 0 /G 1 arrest (54), and the elimination of EBNA-3 results in cell death (55) in lymphoblastoid cell lines. EBNA-3 directly interacts with AhR and enhances its transactivational function via the ligand-activated AhR (56). TCDD-activated AhR induces cell cycle arrest at G 1 , accompanied by the increased expression of the CDK2 inhibitor p27 kip1 (57).…”

Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?

“…In addition to premature degeneration of the thymus caused by the action of activated AhR in the earliest stages of life, [69][70][71] there is further preclinical evidence to support this concern, such as an affinity with Epstein-Barr virus in determining Hodgkin's lymphoma [84][85][86][87] and modulation of the BRCA-1 gene for breast cancer. 98 The 2% annual increase in the incidence of childhood tumors registered over the last 10 years in Italy, the increase in leukemias, lymph omas, and sarcomas in young people/adults, and the 1% increase in the incidence of breast cancers in the age group <45 years (1998-2005) may be related to the abovementioned mechanisms.…”

AIP and its interacting partners

“…In one, it was shown by a co-immunoadsorption assay, that the PPIase-like domain of AIP does not bind, or binds only very weakly, the cytoplasmic dynein (Galigniana et al 2002). In another study, it was demonstrated that the well-documented AIP-mediated cytoplasmic retention of the AhR (Kazlauskas et al 2000, 2002, LaPres et al 2000, Kashuba et al 2006 involves the anchoring of the complex to actin filaments (Berg & Pongratz 2002). By co-IP experiments, this interaction was proved to involve a direct binding of AIP to actin and also to take place only in the non-activated AhR complex, because TCDD treatment induces the release of the complex from actin (Berg & Pongratz 2002).…”

“…This hypothesis was further supported by a following demonstration from the same group that besides AIP, EBNA-3 can also directly interact with the AhR, with AIP enhancing the stability of the complex. As a result of this association, an enhanced transcription of AhR-responsive genes has been observed (Kashuba et al 2006). …”