Evolutionary Conservation and Characterization of The Metazoan Amino Acid Response
Maja Edenius, Ph.D., 2018
Malcolm Whitman, Co-Advisor
Mark Hahn, Co-Advisor
Signaling pathways that respond to stress and sense nutrient availability are highly conserved throughout eukaryotes. In mammalian cells, these pathways have evolved to regulate immune responses. Interestingly, components of these pathways can be found in plants, yeast and nematodes. The Amino Acid Response (AAR) pathway, an ancient response to the cellular accumulation of uncharged tRNA, is part of the larger Integrated Stress Response (ISR) in mammals. Despite its integral role in stress adaptation, the ISR has not been studied in early diverging animals. I have identified a highly conserved phosphorylation site in the protein eIF2α, the signature ISR effector, which allowed me to characterize the ISR in the basal metazoan, Nematostella vectensis, revealing that the core components of the mammalian ISR were present over 550 million years ago in the common ancestor of cnidarians and bilaterians. Additionally, our lab has discovered a novel branch of the AAR pathway. Using the evolutionary conservation of this pathway in model organisms, I have identified GCN1 as the branch point linking the signal generation components of the AAR pathway to downstream therapeutic effects in mammalian cells. I then used transcriptomic and protein interaction analyses to begin to understand the scope and mechanisms of this pathway.