The endoplasmic reticulum (ER) is the cellular organelle primarily responsible for the ability of cells to regulate secretory protein homeostasis (proteostasis). Deficiencies in the ER proteostatic network are implicated in cancer, metabolic disorders, inflammatory diseases, and an assortment of etiologically-diverse neurodegenerative disorders. In order for eukaryotes to maintain proper proteostasis in the ER and throughout the secretory pathway, mammalian cells have evolved the unfolded protein response (UPR), a stress-responsive signaling pathway comprising three distinct stress sensors and signaling arms. Stress-associated activation of all three arms of the UPR induces the expression of chaperones, activates autophagy, alters lipid biosynthesis, as well as influencing pro-apoptotic / pro-survival signaling pathways. In this proposal, I seek to understand how pharmacologic or genetic arm- selective activation of the UPR in the absence of stress influences autophagy and the lipid composition of membranes. I will characterize the induction of autophagy and its key enzymes after administrating our chemical genetic and pharmacologic activators of the UPR (Specific AIM 1), either in isolation or in combination. Autophagy regulation is a key process in proteostasis and its induction can promote pro-survival and amelioration of aggregation-associated degenerative diseases. In addition, I will explore the effect of pharmacological and genetic activation of the ATF6 and/or XBP1 arms of the UPR on membrane lipid composition (Specific AIM 2) and the interplay between lipid composition and UPR modulation. Recent evidence suggests that lipid homeostasis may play a role in UPR regulation and represents a novel point of control, which could ultimately be useful therapeutically.
(Public Health Relevance) The ability to modulate autophagy and lipid homeostasis through the unfolded protein response (UPR) stress-responsive signaling pathways is desirable to understand, as the UPR could have a wider role than is currently appreciated in ameliorating proteinopathies. Toward this end, I will systemically characterize the effect of arm- selective UPR activation on autophagy induction and alterations in membrane lipid composition. Currently there are 35 million people diagnosed with neurodegenerative disorders alone, generating a fiscal impact of 1.1 trillion dollars per year.
