Host-virus interactions in KSHV-related malignancies: evaluating the role of STIP1 as a therapeutic target
Medical Research Council
Rhodes University
Molecular chaperones are essential for protein homeostasis. Hsp90 and Hsp70 function as broad host factors for viral protein folding and are essential for both KSHV latent and lytic replication cycles. As such, we believe KSHV is exquisitely sensitive to perturbations in molecular chaperone systems and inhibition of these pathways is a viable therapeutic strategy. However, targeting molecular chaperones directly is not without issue, due to cells having the ability to circumvent chaperone inhibition by activating alternative stress pathways. For example, resistance to the cellular stress response triggered by Hsp90 inhibition can be overcome by upregulating other chaperones, including Hsp70. To circumvent this issue, we will target alternative components of the stress complexes. Co-chaperones are accessory proteins that fine-tune the function of Hsp70-Hsp90 complexes. Specifically, the co-chaperone STIP1 (also known as HOP) couples the de novo and stress-related protein folding pathways of Hsp70, to the conformational regulation cycle of Hsp90. Therefore, inhibiting STIP1 function is a potential mechanism to simultaneously perturb both Hsp70 and Hsp90 function in viral infection. Our preliminary data suggest that STIP1 is required for survival of latently KSHV infected PEL cells and production of lytic virions. During lytic KSHV replication we determined that STIP1 become enriched in host networks regulating translation and ribosome biogenesis, cytoskeletal remodelling, and metabolism, all of which are necessary for KSHV infection. In addition, four KSHV-encoded proteins were associated with STIP1 during lytic replication. Based on this, this project will aim to understand the mechanisms by which STIP1 regulates the identified host and viral pathways, while concurrently extending the analysis of STIP1 as a therapeutic target in KSHV-infected cells and identifying hit compounds that inhibit STIP1 which could be developed into antiviral agents in future.
2.1 Biological and endogenous factors / Research Grant