Regulation of proteasome assembly and activity in health and disease

Abstract

The proteasome degrades most cellular proteins in a controlled and tightly regulated manner and thereby controls many processes, including cell cycle, transcription, signalling, trafficking and protein quality control. Proteasomal degradation is vital in all cells and organisms, and dysfunction or failure of proteasomal degradation is associated with diverse human diseases, including cancer and neurodegeneration. Target selection is an important and well-established way to control protein degradation. In addition, mounting evidence indicates that cells adjust proteasome-mediated degradation to their needs by regulating proteasome abundance through the coordinated expression of proteasome subunits and assembly chaperones. Central to the regulation of proteasome assembly is TOR complex 1 (TORC1), which is the master regulator of cell growth and stress. This Review discusses how proteasome assembly and the regulation of proteasomal degradation are integrated with cellular physiology, including the interplay between the proteasome and autophagy pathways. Understanding these mechanisms has potential implications for disease therapy, as the misregulation of proteasome function contributes to human diseases such as cancer and neurodegeneration.

Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

“…We discovered that OTUD7A regulates the steady‐state expression level of the PA28 proteasome regulator and α‐ and β‐subunits. In cells, protein degradation is achieved by two systems: the ubiquitin‐proteasome system and the autophagy‐lysosome system (reviewed in Rousseau and Bertolotti) . Proteins are targeted to the proteasome either through ubiquitination, usually in the form of lysine 48‐linked polyubiquitin chains, or by the presence of an unstructured protein regions .…”

“…In cells, protein degradation is achieved by two systems: the ubiquitin‐proteasome system and the autophagy‐lysosome system (reviewed in Rousseau and Bertolotti) . Proteins are targeted to the proteasome either through ubiquitination, usually in the form of lysine 48‐linked polyubiquitin chains, or by the presence of an unstructured protein regions . The eukaryotic 26S proteasome is a complex that consists of two different subcomplexes: the 20S core particle and the 19S regulatory particle (RP) .…”

“…The eukaryotic 26S proteasome is a complex that consists of two different subcomplexes: the 20S core particle and the 19S regulatory particle (RP) . Additional regulatory complexes including PA28 composed by heteroheptamers can substitute the RP to assemble alternative forms of the proteasome α and β subunits …”

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

“…The Ubiquitin‐proteasome‐system (UPS) is the main non‐lysosomal proteolytic pathway for the degradation of misfolded, altered or short‐lived proteins in eukaryotes. It exerts a crucial role in cellular protein turnover e. g. the production of building blocks for the de novo synthesis of proteins and controls several cellular functions such as protein homeostasis, proliferation, apoptosis, signal transduction and antigen production . The ultimate proteolytic component of the UPS is the large, cylindric 26 S proteasome complex, consisting of two regulatory particles (19 S caps) and the 20 S proteasome core particle (CP), being responsible for the proteolysis of the designated proteins.…”

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses

“…Box I details the molecular machinery that underlies constitutive and inducible autophagy responses, and Box II describes the special types of autophagy, namely, secretory autophagy and mitophagy. Autophagy is essential for physiological equilibrium in humans, and when this equilibrium is altered or destroyed, a series of disorders will occur, leading to various forms of morbidity, such as injury, infection, and cancer . Moreover, the process of autophagy interacts with multiple signaling pathways; thus, modulation of autophagy may be a promising and even necessary alternative option for disease treatment.…”