Protein quality control and elimination of protein waste: The role of the ubiquitin–proteasome system

Abstract

Mistakes are part of our world and constantly occurring. Due to transcriptional and translational failures, genomic mutations or diverse stress conditions like oxidation or heat misfolded proteins are permanently produced in every compartment of the cell. As misfolded proteins in general lose their native function and tend to aggregate several cellular mechanisms have been evolved dealing with such potentially toxic protein species. Misfolded proteins are mostly recognized by chaperones on the basis of their exposed hydrophobic patches and, if unable to refold them to their native state, are targeted to proteolytic pathways. Most prominent are the ubiquitin-proteasome system and the autophagic vacuolar (lysosomal) system, eliminating misfolded proteins from the cellular environment. A major task of this quality control system is the specific recognition and separation of the misfolded from the correctly folded protein species and the folding intermediates, respectively, which are on the way to the correct folded state but exhibit properties of misfolded proteins. In this review we focus on the recognition process and subsequent degradation of misfolded proteins via the ubiquitin-proteasome system in the different cell compartments of eukaryotic cells. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

The San1 Ubiquitin Ligase Functions Preferentially with Ubiquitin-conjugating Enzyme Ubc1 during Protein Quality Control

“…Furthermore, mutations in several key enzymes that promote mitophagy through ubiquitylation-specific mechanisms have been found in patients with Parkinson disease (32)(33)(34). Finally, inclusions associated with Huntington disease are localized to the nucleus, suggesting a breakdown of nuclear PQC processes in those patients (35,36).…”

“…Furthermore, mutations in several key enzymes that promote mitophagy through ubiquitylation-specific mechanisms have been found in patients with Parkinson disease (32-34). Finally, inclusions associated with Huntington disease are localized to the nucleus, suggesting a breakdown of nuclear PQC processes in those patients (35,36).Nuclear PQC in the budding yeast Saccharomyces cerevisiae is controlled by the San1 ubiquitin ligase (29, 37). San1 contains highly disordered regions that identify misfolded substrates by binding to exposed hydrophobic stretches on the substrate (38 -43).…”

Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice

“…UPS plays an important role in maintaining the quality and homeostasis of proteins. In the UPS process, a target protein is tagged with ubiquitin, and the ubiquitinated protein is degraded in proteasome complexes (Amm et al, 2014). Three different enzymes regulate UPS.…”

Nuclear factor erythroid-2 related factor 2 Nrf2 -mediated protein quality control in cardiomyocytes

“…Soluble misfolded proteins in the cell are primarily degraded by the UPS. (6,8). Ub is the first and best studied modifier protein that can be covalently linked to other proteins via an isopeptide bond.…”