title: Induction of Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen by the lytic transactivator RTA: a novel mechanism for establishment of latency.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent contributing to development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman desease. Following primary infection, latency is typically established. However, the mechanism by which KSHV establishes latency is not understood. We have reported that the latency-associated nuclear antigen (LANA) can repress RTA (for replication and transcription activator) expression by down-regulating its promoter. In this study, we show that RTA is associated with the virion particle. We also show that RTA can activate the LANA promoter and induce LANA expression in transient reporter assays. Additionally, the transcription of RTA correlates with LANA expression in the early stages of de novo infection of KSHV, and induction of LANA transcription is responsive to induction of RTA with an inducible system. This induction in LANA transcription was dependent on recombination signal sequence binding protein Jkappa (RBP-Jkappa), as a RBP-Jkappa-deficient cell line was significantly delayed and inefficient in LANA transcription with expression of RTA. These studies suggest that RTA contributes to establishment of KSHV latency by activating LANA expression in the early stages of infection by utilizing the major effector of the Notch signaling pathway RBP-Jkappa. This describes a feedback mechanism by which LANA and RTA can regulate each other and is likely to be a key event in the establishment of KSHV latency.
authors.affiliation: Department of Microbiology, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kuppers
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Verma
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sharma
authors.forename: Masanao
authors.initials: M
authors.lastname: Murakami
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000956:Antigens, Viral; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000378:metabolism; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins; C109540:latency-associated nuclear antigen