UC Santa Barbara

Productive Kaposi Sarcoma Associated Herpesvirus (KSHV) infection involves translating, folding, and modifying abundant viral proteins in the Endoplasmic Reticulum (ER). The heightened demand for ER function can disrupt ER homeostasis and activate the Unfolded Protein Response (UPR), a collection of stress-signaling pathways in charge of restoring ER homeostasis. Three ER-resident sensors/transducers, the kinase/RNase IRE1, the kinase PERK, and the membrane-bound transcription factor ATF6, govern the UPR. Their activation either promotes adaptation or causes apoptosis if homeostasis is not restored. A master regulator of the UPR and ER function is the HSP70 ER-resident molecular chaperone GRP78/BiP. This abundant chaperone modulates the activation of the UPR sensors and promotes protein folding in the ER lumen to restore homeostasis. Typically, BiP expression is transcriptionally upregulated in response to ER stress by ATF6. However, our results show that lytic reactivation of KSHV in iSLK-219 cells leads to the ATF6-independent accumulation of GRP78/BiP. The upregulation of GRP78/BiP is critical during the lytic cycle as pharmacological inhibition of genetic depletion of GRP78/BiP reduces viral gene expression and viral particle production. Moreover, our results suggest that BiP activity promotes the survival and growth of KSHV-infected B-cells and lymphatic endothelial cells, and that KSHV-infected cells are uniquely sensitive to a BiP inhibitor, HA15. Inhibition of BiP also leads to the reduction in replication of other DNA viruses, including the beta-herpesvirus human cytomegalovirus (HCMV), the alpha-herpesvirus herpes simplex virus 1 (HSV-1), and the poxvirus vaccinia virus (VV), indicating that the pro-viral role for BiP is not exclusive for KSHV. Our results highlight BiP as a promising target for developing broad-spectrum antivirals and potential therapies for treating KSHV-related malignancies.