title: Carboxyl-terminal amino acids 1052 to 1082 of the latency-associated nuclear antigen (LANA) interact with RBP-Jκ and are responsible for LANA-mediated RTA repression.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is closely associated with several malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV can establish lifelong latency in the host, but the mechanism is not fully understood. Previous studies have proposed a feedback model in which the viral replication and transcription activator (RTA) can induce the expression of the latency-associated nuclear antigen (LANA) during early infection. LANA, in turn, represses transcription and RTA function to establish and maintain KSHV latency. The interaction between LANA and the recombination signal sequence binding protein Jκ (RBP-Jκ, also called CSL), a major transcriptional repressor of the Notch signaling pathway, is essential for RTA repression. In the present study, we show that the LANA carboxyl-terminal amino acids 1052 to 1082 are responsible for the LANA interaction with RBP-Jκ. The secondary structure of the LANA carboxyl terminus resembles the RBP-Jκ-associated module (RAM) of Notch receptor. Furthermore, deletion of the region of LANA residues 1052 to 1082 resulted in aberrant expression of RTA, leading to elevated viral lytic replication. For the first time, we dissected a conserved RBP-Jκ binding domain in LANA and demonstrated that this domain was indispensable for LANA-mediated repression of KSHV lytic genes, thus helping the virus maintain latency and control viral reactivation.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: He
authors.forename: Deguang
authors.initials: D
authors.lastname: Liang
authors.forename: Quanzhi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hongxing
authors.initials: H
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Deng
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016384:Consensus Sequence; D005814:Genes, Viral; D016679:Genome, Viral; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D014779:Virus Replication / Q000502:physiology*
chemical_list: D000596:Amino Acids; D000956:Antigens, Viral; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen