Investigating the role of the unfolded protein response during KSHV lytic replication

Proteins synthesized in the endoplasmic reticulum (ER) need to undergo complex folding events to function correctly. Protein folding defects can be quite toxic to the cell, and have been linked to the pathogenesis of several diseases including diabetes and Huntington's disease (HD). 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. The central player in orchestrating these responses is the X-box binding protein 1 (XBP1) transcription factor, and XBP1 defects have been linked to multiple disease processes. 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. I have discovered that KSHV inhibits XBP1 signaling to promote virus replication. I am currently investigating the molecular mechanism of KSHV-mediated XBP1 inhibition, which appears to involve a specific post-translational modification. Elucidation of the mechanism of viral subversion of the UPR will allow us to better understand its antiviral effect. Viruses are excellent teachers; little is currently known about how post-translational modifications control XBP1 function, and I anticipate that my studies will uncover previously unappreciated fundamental mechanisms of UPR control, which may help us better understand other UPR-related disease processes like HD and diabetes.