Stress Response Pathways Regulating Protein Homeostasis

Project Abstract Cellular stress response pathways are fundamental survival strategies that regulate protein homeostasis and are misregulated in myriad diseases and aging. The mechanisms by which stress response pathways regulate protein homeostasis, how well these mechanisms can perform, and why they fail in disease are major open questions. We explore these questions from both a molecular and biophysical perspective. Over the next five years, we plan to explore how cells detect and respond to defective protein translation, a process called Ribosome-associated Quality Control (RQC). A major focus area will be CArboxyl-terminal Tails (CAT tails), a form of protein synthesis we discovered in which ribosomes elongate defective proteins without guidance from an mRNA template. We will also study biophysical responses to stress, including viscoadaptation, a stress response we discovered in which cells regulate the diffusivity of biomolecules. We have a wealth of expertise and experimental tools to continue our track record of making fundamental discoveries in stress response pathways. Studying cellular stress response pathways at both the molecular and biophysical levels will lead to deep insights into cell survival and the cell biology of disease.