The A20/Itch ubiquitin-editing complex is required for KSHV RTA-induced degradation of vFLIP
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v, 52 pages
DepartmentTowson University. Department of Biological Sciences
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Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-2 herpesvirus that causes lymphoid and endothelial tumors through establishing two replication states: latent and lytic. Latency is maintained in part through expression of viral FLICE inhibitory protein (vFLIP) which inhibits apoptosis and activates nuclear factor-kappaB (NF-KB) signaling. Lytic replication is dependent on the major transactivator of lytic gene expression, replication and transcription activator protein (RTA). vFLIP or NF-KB inhibition results in lytic reactivation, suggesting RTA may have a role in vFLIP stability. Data show RTA destabilizes vFLIP and inhibits vFLIP-induced NF-KB signaling by inducing ubiquitin-proteasome-mediated vFLIP degradation. This thesis provides evidence that the ubiquitin E3-ligase activities of Itch and A20, but not RTA, are required for vFLIP degradation. Immunoprecipitation evidence of A20, Itch, RTA, and vFLIP interaction suggests RTA interacts with the A20/Itch ubiquitin-editing complex to induce vFLIP degradation, inhibiting NF-KB signaling and allowing for lytic reactivation.