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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Latency Abstract 2 DIVERGENCE OF THE NUCLEAR LOCALIZATION SIGNAL WITHIN THE ORF73 LATENCY-ASSOCIATED NUCLEAR ANTIGENS (LANA) OF KSHV AND THE MACAQUE RV1 AND RV2 RHADINOVIRUSES Kellie L. Burnside 1 and Timothy M. Rose 1,2 1 Seattle Children’s Hospital Research Institute and 2 University of Washington, Seattle WA Abstract KSHV LANA is targeted to the nucleus of infected cells by a discrete lysine/arginine-rich nuclear localization signal (NLS; Region I), which allows LANA to enter the nucleus and mediate viral episome persistence, interact with cellular proteins and play a role in latency and tumorigenesis. Conserved homologs of LANA that also exhibit nuclear localization have been identified in KSHV-like macaque herpesviruses belonging to the RV1 and RV2 lineages of Old World primate rhadinoviruses. To characterize the signals mediating nuclear localization, the N-terminal domains of the LANA homologs of the macaque RV1 (RFHVMn) and RV2 (RRV and MneRV2) rhadinoviruses were structurally and functionally compared to the KSHV NLS. A distinct lysine/arginine-rich NLS motif was identified in RFHVMn LANA (Region II) that was adjacent but evolutionarily unrelated to the KSHV NLS. An extended glycine/arginine-rich NLS, spanning 46 residues across Regions I and II, was identified within the RRV and MneRV2 LANAs. Although evolutionarily distinct, the NLS motifs of the human and macaque RV1 rhadinoviruses, KSHV and RFHVMn, both conform to the consensus motif for classical NLSs which interact with importin alpha during nuclear localization. In contrast, the NLSs of the more distantly-related macaque RV2 rhadinoviruses conform to the structure of a number of glycine/arginine-rich NLS motifs which bind directly to importin B during nuclear transport. Like other proteins containing glycine/arginine-rich NLSs, the RV2 LANAs are targeted to the nucleolus. Our findings suggest that the LANA homologs of the RV1 and RV2 rhadinoviruses may be differentially transported and function in different subnuclear compartments. Presenting author Email: timothy.rose@seattlechildrens.org 22
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Latency Abstract 3 NUCLEOPHOSMIN IS A NOVEL REGULATOR OF KSHV REPLICATION VIA FUNCTIONAL INTERACTIONS WITH VIRAL CYCLIN AND LANA Grzegorz Sarek 1 , Annika Järviluoma 1 , Henna Syrjäkari 2 , Sari Tojkander 2 , Salla Vartia 1 , Marikki Laiho 2,3 , and Päivi M. Ojala 1 1 Genome-Scale Biology Program, Biomedicum Helsinki & Institute of Biomedicine, and the Foundation for the Finnish Cancer Institute, 2 Molecular Cancer Biology Program, Biomedicum Helsinki & Haartman Institute; University of Helsinki, P.O. Box 63, 00014- Univ. of Helsinki, Finland; 3 Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 Abstract During Kaposi's sarcoma herpesvirus (KSHV) latency, viral transcription is restricted to a subset of latent genes. The latency-associated nuclear antigen (LANA) interacts with interphase chromatin together with a variety of cellular factors and it actively represses transcription of the KSHV lytic genes. Viral cyclin (v-cyclin), another latent KSHV gene, transcribed from the same promoter as LANA, is structurally similar to cellular D-type cyclins and forms an active kinase complex with cellular CDK6. Nucleophosmin (NPM) is a multifunctional nuclear phosphoprotein implicated in chromatin organization and transcription control. We have previously demonstrated that exogenous expression of vcyclin causes NPM redistribution from the nucleolus to the nucleoplasm in human osteosarcoma cells, suggesting that v-cyclin and NPM may have a functional relationship. Here, we present evidence that NPM interacts with LANA and is a novel substrate for vcyclin-CDK6 kinase complex in primary effusion lymphoma (PEL) cells. Intriguingly, we establish the first functional link between latent proteins LANA and v-cyclin by demonstrating that phosphorylation of NPM by v-cyclin-CDK6 facilitates interaction between NPM and LANA. Silencing of NPM expression in PEL cells induces an increase in the acetylation of LANA, decreases its association with chromatin, and leads to spontaneous viral lytic reactivation. In addition, we show that NPM depletion in PEL cells abolishes interaction between HDAC1 and core histones suggesting that NPM is involved in the recruitment of HDAC1 during KSHV latent infection. This work establishes NPM as a novel regulator of KSHV replication, which maintains the transcriptional silencing of KSHV lytic genes. Presenting author Email: grzegorz.sarek@helsinki.fi 23
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