K.R.E.D: Decisions Between the ER Retention and Exit of Aberrant Proteins, and Links between ERAD and Human Disease

Kavli Research & Enterprise Discussions (K.R.E.D)

Our Kavli Research and Enterprise Discussion (K.R.E.D) will be given by Jeffrey Brodsky. Jeff holds the position of Avinoff Professor of Biological Sciences at the University of Pittsburgh.

Jeff's talk is entitled "Decisions Between the ER Retention and Exit of Aberrant Proteins, and Links between ERAD and Human Disease".

Date: 6 November 2023

Time: 13:30

Room: Phase 2 - Seminar Room 20-138

This is an event for University staff only.

Seating limited to 60 – please arrive on time if you wish to attend.

The abstract is below.

To maintain protein homeostasis, eukaryotes have evolved a hierarchy of protein quality control checkpoints along the secretory pathway, including endoplasmic reticulum associated degradation (ERAD) and post-ER quality control. Although most aberrant proteins in the secretory pathway are eliminated by ERAD, some misfolded proteins can exit the ER in COPII vesicles and are instead turned over by lysosomal proteases after capture by the ESCRT machinery. Other proteins, particularly those that are aggregation-prone in the ER, can alternatively be degraded by ER-phagy. To date, it remains elusive how misfolded proteins—particularly membrane proteins—are selected for one or more of these different fates. By constructing a group of model substrates and by examining human ion channels and transporters in various model systems, we are beginning to define the requirements for the targeted selection of misfolded proteins in the secretory pathway for one disposal pathway versus another. In addition, we have been able to dissect the molecular underpinnings of why some disease-causing mutations in ion channels and transporters result in disease pathology and how the defects associated with these mutant proteins might be corrected using drugs that target distinct protein quality control pathways.

Biography

Jeffrey Brodsky is the Avinoff Professor of Biological Sciences and the Director of the Center for Protein Conformational Diseases at the University of Pittsburgh, and he holds a secondary appointment in the School of Medicine. Dr. Brodsky received his Ph.D. at Harvard University and performed post-doctoral research at the University of California-Berkeley with Randy Schekman prior to joining the faculty at Pittsburgh in 1994. His research focuses on understanding: (1) how misfolded proteins are recognized and destroyed in the cell, (2) how molecular chaperones mediate protein quality control “decisions”, (3) how cellular stress responses affect protein biogenesis and homeostasis, and (4) how defects in disease-associated protein folding and stress responses might be corrected with drugs. The pursuit of these goals has employed biochemical, cell biological, computational, and genetic tools using a range of models, including yeast, cell culture, and rodents. Early work contributed to the discovery of the ER associated degradation (ERAD) pathway, and ongoing studies are deciphering the mechanisms underlying ER “proteostasis” and its relationship to some of the ~70 human diseases are associated with ERAD.