HOP/STIP1 is required for KSHV lytic replication

Abstract

Kaposi sarcoma associated herpesvirus (KSHV) is a DNA virus that causes Kaposi sarcoma, a cancer of endothelial origin. KSHV uses the activity of host molecular chaperones like Hsp70 and Hsp90 for the folding of host and viral proteins required for productive infection. Hsp70 and Hsp90 chaperones form proteostasis networks with several regulatory proteins known as co-chaperones. Of these, Hsp90-Hsp70 organising protein (HOP) is an early-stage co-chaperone that regulates transfer of folding substrate proteins between the Hsp70 and Hsp90 chaperone systems. While roles for Hsp90 and Hsp70 in KSHV biology have been described, HOP has not previously been studied in this context despite its prominent interaction with both chaperones. Here we demonstrate a novel function for HOP as a new host factor required for effective lytic replication of KSHV in primary effusion cell lines.

Modulators of the Hop-HSP90 Protein-Protein Interaction Disrupt Early-Stage of KSHV Lytic Replication

“…Hop is required for KSHV lytic replication. 37 Having established full-length Hop-HSP90 PPI inhibitory activity in conjunction with Hop engagement in cell lysates, we focused on assessing the impact that PPI inhibitory peptides 1 and 2 would have on the activation of KSHV lytic replication. To address possible cell-penetration limitations, we also generated Arg-8 CPP containing analogues of 1 (CPP-1, Figure 6C) and 2 (CPP-2), in addition to an MAAVD containing control (CPP-19).…”

“…[34][35][36] Recently, we showed that Hop is required for KSHV lytic replication, with Hop depletion resulting in reduced transcription of KSHV lytic genes, reduced viral DNA load and reduced infectious virion production. 37 Rahimi and McAlpine have reported a suite of cyclic peptides whose binding to the HSP90-C-terminal region disrupted PPI formation with Hop, which in turn correlated with inhibition of HSP90-mediated luciferase refolding. 38,39 As an alternative strategy, we and others have sought strategies to disrupt this PPI through compounds which interact with Hop.…”