Review
The proteasomal system

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Abstract

Rising interest in the mechanism and function of the proteasomes and the ubiquitin system revealed that it is hard to find any aspect of the cellular metabolic network that is not directly or indirectly affected by the degradation system. This includes the cell cycle, the “quality control” of newly synthesized proteins (ERAD), transcription factor regulation, gene expression, cell differentiation, immune response or pathologic processes like cancer, neurodegenerative diseases, lipofuscin formation, diabetes, atherosclerosis, inflammatory processes or cataract formation and in addition to that the aging process itself and the degradation of oxidized proteins, in order to maintain cell homeostasis. But also this seems to be only a small aspect of the general view. The various regulator proteins that are able to change the rate or specificity of proteolysis, fitting it out for highly specialized tasks, or the precise regulation of the half-life of cellular proteins by ubiquitin-mediated degradation shape the proteasome and the ubiquitin–proteasome system into a fascinating and essential part of cellular function in the three kingdoms of bacteria, plants and animals.

This review tries to summarize the current knowledge on the proteasome and the ubiquitin–proteasomal system, including the cellular functions of this system.

Introduction

To maintain the cellular functionality and viability, it is important to subject proteins to a defined turnover. In order to realize this, damaged, modified, misfolded proteins or proteins that have become‘ unnecessary must be recognized and degraded. During evolution several systems have developed for this purpose, including the proteasomal system, which is the most important of them, at least in the cytosol. The proteasomal system consists of the 20S “core” proteasome and a set of regulator proteins that can change its activities and specificities. In this review we will describe the current knowledge on structure and assembly of the proteasome its intracellular functions and its role in pathologies.

For simplicity in the following manuscript, the 20S “core” proteasome will be termed as “proteasome”. All other forms will be termed according to the attached regulators.

Section snippets

The 20S proteasome

The 20S “core” proteasome is the main particle of the proteasomal system, a very complex cellular structure involved in the proteolytic degradation of oxidized proteins, life-span regulation of proteins (Dick et al., 1991, Grune et al., 1996, Takeuchi and Toh-e, 1997, Sitte et al., 1998, Friguet et al., 2000, Davies, 2001), protein “quality control” (Schmitz and Herzog, 2004, Lord et al., 2000, Plemper and Wolf, 1999, Hampton, 2002, Brodsky and McCracken, 1999), cell cycle regulation (Takeuchi

Regulation of the 20S proteasome

The highly effective protein degradation machinery of the proteasome must be strictly regulated in order to prevent the uncontrolled degradation of cellular proteins. Therefore, several regulators evolved in order to control the proteasomal recognition and degradation of substrate proteins. The gating of the 20S proteasome requires a regulated entrance of substrates into the proteasome and, there, a controlled opening of the α-rings. Hydrophobic proteins are perhaps able to open the α-subunit

Proteasome and transcription factor degradation

Posttranslational modification of proteins plays an important role in the transcriptional regulation in cells and causes, therefore, changes in gene expressions. Such modifications include phosphorylation or dephosphorylation as reversible processes (Hunter and Karin, 1992) or proteolysis as an irreversible process. Proteasomal degradation regulates numerous transcriptional factors including NFκB, p53, c-jun, β-catenin, E2F-1 and consequently activates or inactivates related gene expression.

Conclusion

As shown in the present review, it is very difficult to find an aspect of cellular life, function or pathology not involving the proteasomal system. The importance of the UPS for the functionality of the cell plays a role hardly to overestimate. Taking into account that early in evolution, like in archaebacteria as T. acidophilum, this system developed, demonstrates that recognition and removal of non-necessary or damaged proteins from a living cell has been required almost from the origins of

Acknowledgement

We thank the The Scientific and Technological Research Council of Turkey and COST B35 for the support.

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