Mechanisms of GPCR-induced Autophagy

G-protein coupled receptors (GPCRs) commonly detect extracellular signals to control cellular responses. In many cases, GPCRs detect stresses that lead to activation of the cellular recycling process called autophagy. In the yeast mating pathway, GPCRs are used to detect and grow towards potential mating partners. The mating pathway initiates autophagy, despite the lack of an external stress. We hypothesize that GPCR activation of autophagy represents a novel negative feedback loop that reduces GPCR signaling through enhanced degradation of the receptor. In Aim1 we will test the hypothesis that pheromone signaling drives selective autophagy rather than bulk autophagy through a combination of Gα activation of PI3 Kinase and other pheromone specific signals. In Aim 2 we will test the hypothesis that pheromone induced autophagy serves as a negative feedback loop to enhance receptor desensitization. These studies will provide a molecular understanding of the interplay between GPCR signaling and autophagy, two systems that are well conserved between yeast and humans and in which yeast research has a long history of providing meaningful advances in the understanding of human biology. The understanding of GPCR and autophagy interactions is important to understanding the potential combinatorial effects of the myriad GPCR and autophagy targeting drugs currently used to treat human disease.