Folding and assembly of proteins synthesized in the endoplasmic reticulum is closely monitored by a quality control apparatus that diverts folding-defective products to the cytosol to be degraded by the ubiquitin-proteasome system by a process known as endoplasmic reticulum-associated degradation (ERAD). The long-term goal of this project is to elucidate the mechanisms by which ERAD recognizes and destroys its targets. In the previous funding period we successfully implemented a large scale functional genomic analysis of the mammalian ERAD system that allowed us to perform unbiased analysis of substrate-selective ERAD in mammals. These data led to critical discoveries about the mechanisms of substrate triage and delivery to the HRD1 dislocon/ligase and the role of unconventional ubiquitin conjugation in coupling dislocation to degradation. The studies proposed in the present application harness state-of-the-art technologies that extend these discoveries and if successful will bring about a detailed molecular-level understanding of triage and quality control in the early secretory pathway. !
Protein quality control (PQC) is the process by which cells monitor and maintain the conformational integrity of their proteome and defects in PQC underlie the pathogenesis of many human diseases. PQC systems ensure that proteins which fail correctly fold or assemble are recognized and degraded by the ubiquitin-proteasome system (UPS). This proposal seeks to elucidate the molecular mechanisms by which such folding-defective proteins are recognized and handed off to the UPS.
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