ChBE Seminar Series: Christina Chan
Tuesday, March 26, 2013
Room 2108 Chemical and Nuclear Engineering Bldg.
Professor Ganesh Sriram
Palmitate Interacts Directly with Kinases to Activate Signaling of ER Stress
George W. Bissell Professor
Department of Biochemistry & Molecular Biology
Michigan State University
Improved understanding of the mechanisms of diseases (e.g., lipotoxicity, steatosis, cancer, etc.) and the identification of effective drug targets require better understanding of how environmental factors (i.e. chemicals, lipids, etc.) modulate cellular processes. Our group had developed an integrative framework that reconstructs networks of active pathways from high throughput data, which helped to identify potential pathways perturbed by saturated fatty acids. Elevated levels of fatty acids have been implicated in numerous diseases, including diabetes, cancer, etc. However, the mechanisms by which elevated levels of saturated fatty acids, namely palmitate, contribute to these diseases are unclear. Our group identified that saturated fatty acids, well studied for their roles in metabolism, can also activate signaling pathways. More recently, we found that palmitate can directly bind to kinase proteins to modulate signaling in cells.
Along those lines, our laboratory has focused on understanding how palmitate is involved in activating endoplasmic reticulum (ER) stress. The ER is a major compartment within the eukaryotic cell responsible for folding of secretory and transmembrane proteins. Research in our laboratory suggests that palmitate could modulate the ER stress response and signaling. A malfunction of the ER stress response caused by aging, genetic mutations, or environmental factors can result in diseases such as diabetes, inflammation, cancer and neurodegenerative disorders including Alzheimer's disease.
This ER stress is sensed by the cells through three ER transmembrane proteins, IRE1α (inositol-requiring enzyme 1 α), PERK (protein kinase RNA (PKR)-like ER kinase), and ATF6α (activating transcription factor 6α). They activate signaling processes to restore ER homeostasis, and are collectively termed the unfolded protein response (UPR). UPR signaling coordinate the cellular response by down-regulating protein translation, enhancing expression of ER chaperone proteins that promote protein refolding, and activating proteases involved in the degradation of misfolded proteins. Through biochemical and biophysical methods (i.e. molecular dynamics simulation, binding, and mutation studies) we found that palmitate binds directly to IRE1α to modulate the activity of this kinase protein. Finally, I will touch upon polymeric delivery platform our laboratory is developing to eventually target these pathways.