Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A

Abstract

Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, includingBurkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV.Epstein-Barr virus (EBV) is a member of the human ␥-herpesvirus family. Greater than 90% of the adult population worldwide is infected with the virus. In the majority of cases, EBV infection is asymptomatic for the lifetime of the host due to cytotoxic T-lymphocyte-mediated targeting of infected cells (42). EBV primarily infects B cells but has also been reported to infect T cells and epithelial cells. Primary infection with EBV during adolescence or adulthood can be accompanied by the development of a self-limiting T-cell lymphocytosis known as infectious mononucleosis. However, EBV is also potentially oncogenic. The virus has been detected in malignancies of lymphoid as well as epithelial origin (41). The EBV genome is detected in most cases of posttransplant lymphoproliferative disease, where patients are immunosuppressed and thus cannot control the proliferation of virus-infected cells (36). Essentially every case of endemic Burkitt's lymphoma (BL) is EBV positive, in contrast with between 10 and 90% of sporadic cases. The virus has also been implicated in cases of Hodgkin's lymphoma, nasopharyngeal carcinoma, and some T-cell lymphomas.The in vitro infection of primary B cells with EBV leads to the establishment of immortalized lymphoblastoid cell lines (LCLs). The cooperative actions of several EBV genes contribute to this effect by generating survival and proliferation signals (56). Activation of the transcription factor NF-B and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway has been shown to play an important role in the regulation of survival and proliferation of B cells (6). While many of the targets of NF-B have been characterized, the nuclear targets of PI3K are relatively poorly characterized for EBV-immortalized B cells.Proapoptotic forkhead box class O (FoxO) transcription factors are direct targets of PI3K-mediated signal transduction in a variety of cell systems. Phosphorylation of members of this transcription factor f...

Epstein-Barr Virus Latent Membrane Protein 1 Represses DNA Repair through the PI3K/Akt/FOXO3a Pathway in Human Epithelial Cells

“…In another study, FOXO1 has been shown to be downregulated in EBV-infected B cells. Two EBV proteins, LMP1 and LMP2A, may contribute to this repression by PI3K-mediated nuclear export, by inhibition of FOXO1 mRNA expression, and by alteration of posttranslational modifications (60). However, as we show here, it seems that the LMP1-mediated PI3K/Akt pathway plays the major role in FOXO3a inactivation because the PI3K inhibitor LY294002 can block LMP1-induced FOXO3a phosphorylation and relocalization.…”

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

“…5,6 The main regulator of GC formation BCL6 is also a FOXO target. 36 Although we observed FOXO1 repression in some of the NHL cases, the strong FOXO1 expression in most of NHL entities was surprising because Foxo1 was reported to be the main mediator of physiologic B-cell death in mouse. 8 Moreover, the functionally and structurally similar Foxo3 was reported to repress Myc-induced B-cell lymphomagenesis in a mouse model.…”

Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

“…Proper splicing and synthesis of Ikaros requires FoxO1, which is negatively regulated by phosphatidylinositol 3-kinase (PI3K) signaling (82). EBV-encoded LMP1 and LMP2A downregulate FoxO1 expression via PI3K-mediated nuclear export (83). The EBV latency III program also induces the expression of cellular microRNA-27a (miR-27a), which targets Ikaros mRNA (84,85).…”