Herpesvirus subversion of unfolded protein responses

Proteins synthesized in the endoplasmic reticulum (ER) need to undergo complex folding events to function correctly. When ER folding capacity is overwhelmed a stress management program called the unfolded protein response (UPR) is initiated in attempt to alleviate this potentially fatal stress. The UPR has evolved to sense the accumulation of misfolded proteins in the ER and deliver a signal to the nucleus to increase the expression of genes that (i) increase ER folding capacity and (ii) destroy terminally misfolded proteins. If stress cannot be resolved then the UPR initiates a cell death response. There is emerging evidence that the UPR is a node of control subverted by viruses to support viral replication and aspects of pathogenesis, but specific mechanistic details remain unclear. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of the AIDS defining cancer, Kaposi's sarcoma. We discovered that KSHV usurps host UPR processes to promote viral replication. Though this study, we will identify the viral genes responsible for controlling the host UPR system, and we will figure out how they work.