The cellular stress response represents an essential mechanism that enables cells to adapt to an array of environmental and physiological conditions. Given the importance of these adaptive responses, it comes as no surprise that dysregulation of the stress response has been strongly implicated in various diseases including infection, neurodegenerative diseases, and cancer. The findings presented in this thesis reveal novel aspects of the cellular response elicited by stress stimuli including nutrient starvation, proteotoxic stress and infection by intracellular bacterial pathogens. We first highlight that various components of the machinery responsible for mRNA splicing undergo dynamic reorganization into cytoplasmic granules known as U snRNA (U) bodies during metabolic stress and infection. The formation of U bodies during stress is accompanied by an overall decrease in splicing components, including the U snRNAs that are essential for mRNA splicing. Furthermore, we report global transcriptional reprogramming of a core group of stress-related genes in intestinal epithelial organoids in response to endoplasmic reticulum (ER) stress and nutrient starvation, including transcription factors, chemokines, and genes involved in inflammation. The landscape of alternative splicing (AS) was also strongly affected by cellular stress, and we report the existence of a conserved mechanism to regulate the expression of splicing and RNA processing genes that involves the coupling of AS and nonsense-mediated decay (NMD). Lastly, this thesis underscores the importance of stress response pathways in the maintenance of cellular homeostasis and survival by highlighting a novel role for the natural compound isoginkgetin as an inhibitor of the 26S proteasome. Disruption of protein homeostasis via isoginkgetin impairs the ability of cancer cells to mount stress responses and sensitizes various cancer cell types to apoptotic cell death upon nutrient starvation. Taken together, the results of this research will contribute to the overall understanding of the mechanisms underlying the cellular adaptation to stress and will aid in the development of novel therapeutics for diseases in which critical arms of the stress response are dysregulated.Ph.D.2019-12-19 00:00:0
