Viral Control of Autophagy to Reprogram the Host Cell Secretome

Viruses are incredible tools that teach us how our cells work. In my lab, we study the virus, Kaposi's sarcoma-associated herpesvirus (KSHV). This virus causes a rare skin cancer called Kaposi's sarcoma (KS). My lab is interested in how this virus changes cells that comprise blood vessels, called endothelial cells, to make them secrete proteins that are called inflammatory cytokines, that promote the cancer KS. I have discovered that KSHV targets granules called processing bodies (PBs) that play an important role in controlling inflammatory cytokine production (Corcoran et al. 2015 PLoS Path. 11:e1004597). My lab now has exciting new evidence that connects the disappearance of PBs to the process of autophagy, which literally means 'self-eating'. Autophagy is an evolutionarily conserved mechanism that permits cells to survive the stress of starvation by promoting the degradation and recycling of a variety of cellular structures, thereby providing essential cellular building blocks and energy for survival. Autophagy has also been shown to regulate inflammatory cytokine production; however how this occurs is not clear in most cases. My compelling preliminary evidence connects autophagy increases with the disassembly of PBs and increased inflammatory cytokine production. This is the first evidence suggesting the coordinated regulation of autophagy and PBs controls inflammation in our cells. Impact and Significance: My lab has made a fundamental discovery about how inflammatory cytokine expression is regulated. Inflammatory cytokines are aberrantly produced in many disorders in addition to KS, such as rheumatoid arthritis and many other cancers. Increasing our knowledge of how autophagy and PBs are functionally linked will help develop new treatments to limit inflammation in many situations.