Ubiquitination and deubiquitination: a Yin-Yang cycle in protein quality control at the endoplasmic reticulum

Director's Seminar Series The endoplasmic reticulum (ER) is the major site of protein biosynthesis in eukaryotes. Polypeptides entering the ER frequently encounter folding problems, resulting in aggregation-prone, misfolded proteins. To preserve ER homeostasis, eukaryotic cells have evolved a conserved quality control pathway termed ER-associated protein degradation (ERAD) or retrotranslocation, which eliminates unwanted proteins of the ER by exporting them into the cytosol for degradation by the ubiquitin proteasome system. Defects in ERAD result in accumulation of misfolded proteins and cause ER stress. ER stress has been implicated in the pathogenesis of many human diseases including type 2 diabetes and several types of neurodegenerative diseases. The retrotranslocation system is also hijacked by certain viruses to destroy folded cellular proteins essential for anti-viral defense. This allows viruses to evade host immune surveillance. The molecular mechanism by which retrotranslocated substrates are targeted to the proteasome has been elusive. Recent studies from my laboratory reveal a complex interplay between ubiquitin ligases, deubiquitinating enzymes, and a chaperone holdase in this process.Air date: 4/12/2013 12:00:00 PM
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