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Date of Award
ICP0 is one of the immediate early viral proteins and essential for HSV-1 replication in low MOI infection. ICP0 is involved in manipulating various cellular pathways and attenuating their inhibitory functions on viral replication through either protein-protein interaction or using its E3 ligase activity to degrade restrictive factors. Upon infection, HSV-1 viral DNA is injected into the nucleus and found to be closely associated with ND10. ND10 association with viral DNA causes the repression of viral gene expression, which is inactivated by ICP0. HSV-1 employs ICP0 to target key ND10 components PML and Sp100 for proteasomal degradation, leading to the destruction of ND10 and dispersion of inhibitory ND10 components. Therefore, viral gene expression and viral replication are enhanced.
First, I investigated the ICP0 dynamic interaction with ND10, especially the ND10 fusion step. ND10 fusion step is presumably regulating ICP0 access to its substrate and hence critical for ICP0 to execute its function. Through deletion mapping and confocal microscopy, I have identified three redundant and proline-rich segments in ICP0 that independently drive ICP0 to fuse with ND10. This study is the necessary groundwork for understanding the protein-protein interaction during ND10 fusion.
Next, I identified the elements in ICP0 that control its substrate recognition, especially differential degradation of PML isoforms. Through deletion mapping and half-life assay, I have identified ICP0 uses at least two different mechanisms for targeting PML isoforms. This study helps to understand the sequences in ICP0 that are essential for its substrate differentiation and regulation of its E3 ubiquitin ligase activity.
Overall, I have identified the sequences in ICP0 governing interaction between ICP0 and ND10 and regulating degradation of ND10 components through both studies. These studies laid the foundation for understanding ICP0 coordination of its multifunction and provide critical and novel information for designing possible drug targets to block HSV-1 infection.
Zheng, Yi, "Targeting Host Defense: The Dynamic Nd10 Interaction And The Differential Substrate Recognition Of Hsv-1 Icp0" (2017). Wayne State University Dissertations. 1905.