Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling

Abstract

Infection by Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) isK aposi's sarcoma (KS), the most common neoplasm of untreated AIDS patients, is a complex lesion characterized by endothelial proliferation, neoangiogenesis, and inflammatory cell infiltration (1, 2). In 1994, a novel herpesvirus, now termed KS-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), was identified in KS lesions (3), and compelling epidemiological and molecular evidence strongly links KSHV infection to KS tumorigenesis (see refs. 4 and 5 for review). Like all herpesviruses, KSHV deploys two alternative genetic programs in infection: (i) latency, in which only a handful of viral genes is expressed and no infectious progeny are produced, and (ii) lytic infection, in which most viral genes are expressed in an ordered cascade, viral DNA is amplified, and infectious virions are released. Examination of KS biopsy specimens shows that KSHV infection is localized to the tumorous endothelial (spindle) cells (6), the majority of which are latently infected (7). A small subpopulation, however, are lytically infected (7), and recent evidence suggests that both latency and lytic infection contribute importantly to KS pathogenesis. The latency program encodes numerous proteins that can affect cell survival and proliferation in vitro (8-12), whereas the lytic cycle encodes a variety of signaling proteins that can either directly mediate angiogenesis and inflammation (13-16) or induce expression of host proteins that can do likewise (17). In addition, KSHV latency is somewhat unstable, in that proliferating cells frequently give rise to uninfected segregants (A. Grundhoff and D.G., unpublished results); ongoing lytic infection also serves as a source of virus that can sustain the population of latently infected cells via de novo infection͞reinfection.In most cultured cells, the default pathway of KSHV infection is latency; that is, newly infected cells do not express the full lytic cascade, but rather maintain the viral DNA in the nucleus as a low copy number, circular episome whose expression is tightly restricted (18,19). Little is known about the mechanisms by which latency is established. Formally speaking, the absence of lytic gene expression might be due to the absence of one or more positive regulators, or to the presence of active repression (or both).A single KSHV lytic-cycle viral gene (ORF50) controls the switch from latency to lytic replication (20,21). Its product, the replication and transcription activator (RTA), is a transcription factor that is both necessary (22) and sufficient (20,22,23) to trigger lytic reactivation. The mechanisms by which KSHV RTA acts have been extensively studied in cells transiently transfected by reporter gene constructs. RTA harbors a potent C-terminal activation domain, deletion of which results in a loss of transactivation activity (22,24). In addition, it has an N-terminal DNA-binding motif that can mediate sequence-specific DNA binding, and high-affinity sites for RTA recognition have been iden...

Modulation of Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Activator Transactivation by Interferon Regulatory Factor 7

“…The direct binding of RTA to specific promoter RRE sequences was shown to contribute to the activation of various early and late viral genes during lytic replication, and the expression of these genes is modulated by the DNA binding affinity of RTA for the various target sites (42). A number of cellular and viral coactivators have been described as playing a role in RTA-mediated transcription activity, where most were found to enhance lytic gene expression in the presence of RTA (13,14,23,24,46,47). These RTA-interacting factors may also play a role in modulating the binding affinity of RTA to its target sites.…”

“…The RRE of ORF 57 was previously characterized and was found to be a target for either direct RTA binding or indirect binding mediated by cellular factors, such as RBPj (23,24,28,42). The RRE has been mapped to a 40-bp region which contains a consensus sequence found in the promoters of other RTA-responsive genes, such as K8 (29,45).…”

CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

“…Then, EBV can manipulate cellular NICD target gene expression and also contribute to the expression of EBV genes by recruiting cellular Rbpjκ onto its promoter regions. In parallel, the KSHV product, replication and transcription activator protein (RTA) [105], is also known to exploit Notch signaling in a similar manner as EBV in host cells. The establishment of a lifelong persistent infection in the host is a critical strategy for the survival of the virus.…”

Tpl2/AP-1 Enhances Murine Gammaherpesvirus 68 Lytic Replication

“…Because of the critical role that RTA and/or ZTA plays in initiating the whole lytic replication cascade, a number of studies have focused on cellular factors that regulate RTA and ZTA. For example, several cellular factors, such as NF-B, PARP-1, and KSHV-RTA-binding protein (K-RBP), were shown to inhibit gammaherpesvirus lytic replication through inhibiting RTA expression or activity (4,24,64), whereas RBP-J (CSL or CBF1), CREB-binding protein (CBP), SWI/SNF, and CCAAT/enhancer-binding protein-␣ (C/EBP␣) have been found to up-regulate RTA's transcriptional activity and lytic replication (22,23,35,36,57).…”