The first open-reading frames of Kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus and their contributions to the viral life-cycle Public Deposited

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  • March 22, 2019
Creator
  • Tomlinson, Christine C.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's Disease. The simian homologue of KSHV, rhesus monkey rhadinovirus (RRV), is highly related to KSHV. The first open reading frames of KSHV and RRV encode for proteins K1 and R1, respectively. Although only 17% similar at the amino acid level, K1 and R1 function similarly, scoring positively in a number of cellular transformation assays and encoding an immunoreceptor -tyrosine-based activation motif (ITAM). Both proteins are capable of activating B lymphocyte signal transduction and interacting with the major B cell kinase, Syk. Expression of K1 in B lymphocytes was found to activate the PI3K/Akt pathway and inhibit PTEN, leading to the inhibition of FKHR transcription factors, key regulators of cell cycle progression and apoptosis. K1 expression inhibited apoptosis induced by FKHR proteins and the FasL/Fas receptor pathway. Expression of K1 promotes cell survival pathways and contributes to KSHV pathogenesis by preventing virally infected cells from undergoing premature apoptosis. Recent evidence suggests that receptor signaling not only occurs at the cell membrane, but from intracellular compartments. K1 was found to internalize in a clathrin-dependent manner, trafficking from the early endosome to the recycling endosome. By blocking signaling of PI3K or Syk, the rate of K1 internalization was diminished. Additionally, blocking clathrin-mediated endocytosis inhibited downstream signaling by K1 to Akt. The above phenomena are dependent on a functional ITAM of K1. This suggests that K1 signaling is strongly associated with internalization. In B-cells, K1 co-internalizes with the BCR, suggesting that K1 scavenges the BCR from the surface. In order to discern what role R1 plays in the virus life-cycle, the R1 ORF was deleted from the RRV genome, by insertion of a GFP expression cassette. By PCR and Southern blot analysis, this virus is identical to the wild-type virus, except for insertion of the transgene. This virus will be used to analyze the contribution of R1 to lytic replication, establishment of latency, and reactivation from latency. Additionally, this virus can be used to observe the role R1 plays in the development of disease in vivo.
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  • In Copyright
Advisor
  • Damania, Blossom
Degree granting institution
  • University of North Carolina at Chapel Hill
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