The A20/Itch ubiquitin-editing complex is required for KSHV RTA-induced degradation of vFLIP
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Date
2014-07-10
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Towson University. Department of Biological Sciences
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Citation of Original Publication
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There are no restrictions on access to this document. An internet release form signed by the author to display this document online is on file with Towson University Special Collections and Archives.
There are no restrictions on access to this document. An internet release form signed by the author to display this document online is on file with Towson University Special Collections and Archives.
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Abstract
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.