Intracellular Dynamics of the Ubiquitin-Proteasome-System

Abstract

The ubiquitin-proteasome system is the major degradation pathway for short-lived proteins in eukaryotic cells. Targets of the ubiquitin-proteasome-system are proteins regulating a broad range of cellular processes including cell cycle progression, gene expression, the quality control of proteostasis and the response to geno- and proteotoxic stress. Prior to degradation, the proteasomal substrate is marked with a poly-ubiquitin chain. The key protease of the ubiquitin system is the proteasome. In dividing cells, proteasomes exist as holo-enzymes composed of regulatory and core particles. The regulatory complex confers ubiquitin-recognition and ATP dependence on proteasomal protein degradation. The catalytic sites are located in the proteasome core particle. Proteasome holo-enzymes are predominantly nuclear suggesting a major requirement for proteasomal proteolysis in the nucleus. In cell cycle arrested mammalian or quiescent yeast cells, proteasomes deplete from the nucleus and accumulate in granules at the nuclear envelope (NE) / endoplasmic reticulum (ER) membranes. In prolonged quiescence, proteasome granules drop off the NE / ER membranes and migrate as stable organelles throughout the cytoplasm, as thoroughly investigated in yeast. When quiescence yeast cells are allowed to resume growth, proteasome granules clear and proteasomes are rapidly imported into the nucleus.Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm.Most of our current knowledge is based on studies in yeast. Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells which comprise the majority of our body’s cells.

Stress induced nuclear granules form in response to accumulation of misfolded proteins in Caenorhabditis elegans

“…This result adds to a growing number of reports that suggest that protein degradation is taking place in the nucleus (reviewed in [49]). In yeast, it has been reported that degradation of some short-lived proteins occurs by first importing them into the nucleus where they are degraded by nuclear proteasomes [10].…”

Membrane potential regulates the dynamic localisation of mammalian proteasomes

“…This suggests that other proteasomal particles remain dispersed through the cell to ensure that general protein turnover and homeostasis are not disrupted. Given that different cell types have distinct resting membrane potentials, proteasome localisation and movement might be very different between cell types and account for some of the reported differences (reviewed in [ 17 ]). Small changes in local proteasome level could therefore be sufficient to activate physiological processes sensitive to degradation.…”

“…Various subcellular localisations of proteasomes have been reported, depending on the type of cells, method of fixation and imaging technique used [15][16][17][18] . Early imaging studies on immunostained mammalian cells found that proteasomes preferentially localised to the ER/nuclear envelope 19,20 .…”

Inhibition or Stimulation of Autophagy Affects Early Formation of Lipofuscin-Like Autofluorescence in the Retinal Pigment Epithelium Cell

“…The proteasome system (sometimes referred to as the ubiquitin-proteasome system) is a cellular pathway responsible for degrading the majority of the short-lived cells and abnormal proteins, and operates through the 26S proteasome [44]. In contrast, the autophagy system is mostly responsible for the degradation of long-lived proteins and cellular organelles, and operates through lysosomes [45].…”