Molecular host-virus interactions that regulate lytic reactivation of Kaposi's Sarcoma-associated Herpesvirus from latency

The members of the gamma-2 sub-family of the herpesviridae share a remarkable association with the etiology of malignancies. Kaposi?s sarcoma-associated herpesvirus (KSHV) is the most recently discovered human herpesvirus, and has been grouped in this family.? KSHV is the sexually-transmitted agent necessary for Kaposi?s sarcoma (KS) tumor development and primary effusion lymphoma (PEL).

Lytic reactivation of KSHV from latency in B cells is crucial for viral dissemination, the pathogenic outcome of the infection, and the site of cancer. We have previously demonstrated that the KSHV ORF (open reading frame) 50 protein (called ?Rta?) is both necessary and sufficient for lytic viral reactivation. We have demonstrated that ORF50/Rta functions transcriptionally as a ligand-independent inducer of the cellular Notch signaling pathway. We hypothesize that ORF 50/Rta may reciprocally participate in abnormal regulation of host genes that are normal targets of RBP-Jk and the Notch signal transduction cascade.

Abnormal induction of the Notch signaling pathway is associated with malignancies. Notch mutations that render the molecule constitutively active are associated with T-cell lymphoblastic leukemias (T-ALL). Epstein-Barr Virs (EBV), another human herpesvirus, expresses a protein that mimics constitutive Notch signaling and is required for EBV transformation of B lymphocytes. We have recently discovered that KSHV Rta?s mechanism of inducing Notch target genes is fundamentally different from the well-studied Notch and EBNA2 proteins. We have found that RBP-Jk is not able to constitutively bind to all promoters having RBP-Jk elements. However, Rta stimulates DNA binding by RBP-Jk to these promoters.
Our current research focuses on the following aspects of host-virus biology:

1. biochemical dissection of Rta?s function as the lytic switch protein,
2. promoter specification of Notch pathway activators in virally infected cells,
3. molecular regulation of progression of KSHV reactivation.
   

Selected Publications

• Bu, W, D Palmeri, R Krishnan, R Marin, VM Aris, P Soteropoulos, and DM Lukac. (2008). Identification of Direct Transcriptional Targets of the Kaposi?s sarcoma-associated herpesvirus (KSHV) Rta Lytic Switch Protein by conditional nuclear localization. J. Virol in press.
  
  
• Palmeri, D, S Spadavecchia, KD Carroll, and DM Lukac. (2007) 
Promoter and Cell-Specific Transcriptional Activation by the Kaposi?s sarcoma-associated Herpesvirus ORF57/Mta Protein. J. Virol.? 81: 13299-13314.
  
  
• Carroll, KD, F Khadim, S Spadavecchia, D Palmeri, and DM Lukac. (2007).? Direct interactions of KSHV/HHV-8 ORF50/Rta protein with the cellular protein Octamer-1 and DNA are critical for specifiying transactivation of a delayed-early promoter and viral reactivation. J. Virol. 81: 8451-67.
  
  
• Bu, W, KD Carroll, D Palmeri, and DM Lukac. (2007).? The Kaposi?s sarcoma-associated Herpesvirus/Human herpesvirus-8 ORF50/Rta lytic switch protein functions as a tetramer. J. Virol. 81(11):5788-806.
  
  
• Lukac, D.M. and Y. Yuan. (2007; Book Chapter). Lytic Replication of Kaposi?s sarcoma-associated Herpesvirus. In Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Ed. A. Arvin, G. Campadelli-Fiume, P. Moore, E. Mocarski, B. Roizman, R. Whitley, and K. Yamanishi. Cambridge University Press.
  
  
• Carroll, KD, W Bu, D Palmeri, S Spadavecchia, S J. Lynch, S A. E. Marras, S Tyagi, and DM Lukac. (2006).? The KSHV lytic switch protein stimulates DNA binding of RBP-Jk/CSL to activate the Notch pathway. J. Virol. 80 (19) 9697-9709.