Convergence of Kaposi's Sarcoma-Associated Herpesvirus Reactivation with Epstein-Barr Virus Latency and Cellular Growth Mediated by the Notch Signaling Pathway in Coinfected Cells

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL).Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). PEL is a body cavity based lymphoma that is rapidly fatal (15,24,37,56,63). Multiple, continuous PEL cell lines were established by culturing clinical samples from PEL patients (13,54,60). These cell lines were the first tissue culture models for KSHV infection (53,60). Approximately 70% of PEL cell lines are coinfected with KSHV and EpsteinBarr virus (EBV) (17).The KSHV lytic switch protein, replication and transcriptional activator (Rta), encoded by open reading frame 50 (ORF50), is both necessary and sufficient for viral reactivation in PEL cells (47,48,65,70). Lytic reactivation requires the formation of a ternary complex between Rta, delayed early promoter DNA, and the host cell's recombination signal binding protein (RBP)-Jk (also known as CSL-1 and CBF1) (11,44,45). RBP-Jk is a sequence-specific DNA-binding protein that is the nuclear effector of the canonical Notch signal transduction pathway (23).Whereas RBP-Jk is required for productive KSHV reactivation (45), it is also required for latent (nonproductive) transformation of primary B cells by EBV (39). In this program, termed latency III, EBV nuclear antigen 2 (EBNA-2) transactivates two EBV promoters by interacting with RBP-Jk. The two promoters express transcripts that encode seven proteins that promote viral persistence by stabilizing the EBV genome, stimulating B-cell growth and expansion, and blocking B-cell apoptosis (39). One of the transforming EBV latency proteins is latent membrane protein 1 (LMP-1). LMP-1 is a constitutively active ortholog of the cellular tumor necrosis factor (TNF) receptor CD40 (55, 68). LMP-1 induces cell proliferation and transformation by engaging multiple signaling pathways including NF-B, TNF receptor-associated factors (TRAFs) 1 to 3, Akt kinase, Jun kinase, c-Rel, and p38 (16, 18-20, 27, 31, 40, 43, 46, 51, 52, 55). EBV transformation also requires transactivation of cellular genes by EBNA-2 in an RBP-Jk-dependent fashion (22,34,38,62,64,71).RBP-Jk's principal role in KSHV and EBV infection is to specify transcriptional targets of Rta and EBNA-2. RBP-Jk also specifies transcriptional targets for the activated form of the cellular Notch receptor (Notch intracellular domain 1 [NICD-1]); despite the apparent mechanistic similarity of NICD-1 transactivation to that of Rta and EBNA-2, these proteins are not always phenotypically interchangeable. For example, NICD-1 and EBNA-2 do not productively reactivate KSHV from latency (11,14,45), and NICD-1 does not fully complement EBNA-2 deficiency in long-term outgrowth of lymphoblastoid cell lines (LCLs) (25,28). Furthermore, the KSHV genome contains 177 RBP-Jk sites and yet, in the absence of de novo protein expression, Rta only transactivates eight KSHV genes * Corresponding author. Mailing address: ICPH E350C, 225 Warren St.,

The Single RBP-Jκ Site within the LANA Promoter Is Crucial for Establishing Kaposi's Sarcoma-Associated Herpesvirus Latency during Primary Infection

“…Our previous work demonstrated that RTA activates LANA expression during the early stages of infection by recruiting RBP-J bound to its cognate sequence within LANA promoter (39). Other groups have also shown that RTA transactivates the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) and latency C promoters (Cp) in uninfected cells and in dually infected PEL cells by forming a complex with RBP-J and its cognate sequence within the promoters (75). Therefore, we postulated that disruption of RBP-J binding to the LANA promoter will have a profound effect on switching of the virus from latent to the lytic replication.…”

Multiple Defects, Including Premature Apoptosis, Prevent Kaposi's Sarcoma-Associated Herpesvirus Replication in Murine Cells

“…Since ectopic RTA expression in mouse cells has earlier been shown to function in the activation of transfected reporter genes (13,14,23), we wondered if the defects observed might have to do with the nature of the chromatinized DNA template. Accordingly, we asked if lytic reactivation would be more efficient if induction was triggered by exposure to histone deacetylase (HDAc) inhibitors like valproic acid or sodium butyrate (N-butyrate).…”

LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma

“…In the present study, the PI3K/Akt signaling pathway was shown to be involved in the induction of survivin expression by LMP-1. Although the Notch and MAPK pathways are activated by LMP-1 in other diseases (30,31), we found that the roles of the Notch and MAPK pathways in NKTL were not obvious. Thus, we can infer that LMP-1 induced survivin expression by activating the NF-κB and PI3K/Akt pathways in NKTL.…”