UCSF

The endoplasmic reticulum (ER) is the main site in the cell for the folding and processing of secreted proteins. Various physiological and pathological processes can overwhelm the protein folding capacity of the ER. This condition, referred to as "ER stress, typically triggers the activation of the Unfolded Protein Response Pathway (UPR). The activation of this pathway results in expansion of the ER, an increase in chaperone proteins, inhibition of cap-dependent translation, and if homeostasis is not reestablished, apoptosis.

ER stress-induced apoptosis, secondary to a buildup of misfolded proteins, leads to cell loss in a number of human degenerative diseases including ALS, Parkinson, and type II diabetes. In contrast, cancer cells and viruses manipulate the cytoprotective aspects of the UPR, aberrantly promoting cell survival. Therefore, understanding how to manipulate the UPR's cytoprotective/cytotoxic threshold could lead to new treatment approaches for a wide variety of unrelated diseases.

Despite its important role in such a wide variety of diseases, the mechanisms underlying ER stress-induced apoptosis are poorly understood. Utilizing an unbiased biochemical system, I have identified the ER stress-induced pro-apoptotic effectors that signal Bax and Bak at the mitochondrion, BID and CRK, and the mechanisms behind their activation up irremediable ER stress.

In addition, the study of viral manipulation of host machinery has historically provided great insight into cellular biology. Viral infection is a biologically relevant system in which to study the cytoprotective/cytotoxic threshold of the UPR. A large lytic virus, such as Kaposi's Sarcoma Herpes Virus (KSHV or HHV-8), must be able to increase the folding capacity of the ER in order to accommodate the acute influx of viral protein during replication, while coordinately inhibiting the apoptotic consequences of intense ER stress. In this study, I have determined that KSHV inhibits UPR signaling through the IRE1 transmembrane kinase/endoribonuclease during lytic infection and is able to expand the ER through a novel function. These findings reveal new insights into the cytoprotective/cytotoxic regulation of the UPR and novel functions of lytic KSHV. These findings have implications for many diseases aside from viral infection, including type II diabetes, cancer, and neurodegeneration.