Description: (taken in part from Costa-Mattioli and Walter, 2020): The integrated stress response (ISR) is an intracellular signaling program that is required for an organism to adapt to a variable environment and maintain health. In response to a variety of environmental and pathological conditions, including protein homeostasis (proteostasis) defects, nutrient deprivation, viral infection, and oxidative stress, the ISR restores balance by reprogramming gene expression. The various stresses are sensed by four specialized kinases that converge on phosphorylation of a single serine on the eukaryotic translation initiation factor eIF2 (gene = EIF2S1). eIF2 phosphorylation blocks the action of eIF2’s guanine nucleotide exchange factor termed eIF2B, resulting in a general reduction in protein synthesis. Paradoxically, phosphorylation of eIF2 also triggers the translation of specific mRNAs, including key transcription factors, such as ATF4. As such, the mechanistic underpinnings of this stress response network lie solidly in the world of post-transcriptional gene regulation at the translational level. This course will delve into the mechanism and methodology behind this essential stress response pathway, aberrations in which cause a myriad of diseases.
Grading: Student presentations of a paper will count toward 75% of the grade. The remaining 25% will be in the form of a concise (1-page) written project that requires answering a qualifying exam-type question based on a literature search and identification of lynchpin experiments.