University of Pittsburgh Department of Biological Sciences Presents:
Friday Noon Seminar Series 2017-2018
Graduate Student: Zhihao Sun
A Model Substrate whose Degradation Pathway is Determined by Aggregation Propensity
Cellular protein homeostasis is maintained by a hierarchy of protein quality control checkpoints, including endoplasmic reticulum-associated degradation (ERAD), which leads to the efficient degradation of misfolded proteins in the ER. Although most aberrant proteins in the ER are degraded by ERAD, some misfolded membrane proteins can escape ERAD and are degraded instead by lysosomal/vacuolar proteases. To date, it remains elusive how ERAD cooperates with post-ER quality control pathways to destroy misfolded membrane proteins. Here, we designed a novel model substrate, SZ*, to investigate how ERAD substrate selection is regulated in yeast. We discovered that SZ* is degraded by both the proteasome and vacuolar proteases, which occurs after ER exit and requires the multivesicular body (MVB) pathway. After interrogating cells with a variety of stresses, we found that both heat-shock and SZ* overexpression increase ERAD targeting. These events correlate with substrate aggregation. In addition, the aggregation of the large, cytosolic misfolded domain in SZ* is concentration-dependent, and both the cytosolic Hsp70 Ssa1 and Hsp40 Ydj1 molecular chaperones are required to maintain substrate solubility. Finally, fusion of this misfolded domain targets a post-ERQC substrate, which is normally routed to the vacuole, for ERAD. Together, we have identified a novel substrate that can be used to investigate ERAD and post-ERQC degradation pathway selection, and show that a misfolded membrane protein with a higher aggregation propensity is preferentially targeted for ERAD.
Friday, February 9, 2018
A219B Langley Hall
12:00 PM Seminar