Role of Proteasomes in Cellular Regulation

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Abstract

The 26S proteasome is the key enzyme of the ubiquitin‐dependent pathway of protein degradation. This energy‐dependent nanomachine is composed of a 20S catalytic core and associated regulatory complexes. The eukaryotic 20S proteasomes demonstrate besides several kinds of peptidase activities, the endoribonuclease, protein‐chaperone and DNA‐helicase activities. Ubiquitin‐proteasome pathway controls the levels of the key regulatory proteins in the cell and thus is essential for life and is involved in regulation of crucial cellular processes. Proteasome population in the cell is structurally and functionally heterogeneous. These complexes are subjected to tightly organized regulation, particularly, to a variety of posttranslational modifications. In this review we will summarize the current state of knowledge regarding proteasome participation in the control of cell cycle, apoptosis, differentiation, modulation of immune responses, reprogramming of these particles during these processes, their heterogeneity and involvement in the main levels of gene expression.

Introduction

Degradation of cellular proteins is a tightly regulated process, carried out by the cascade of the proteasome‐ubiquitin pathway. The 26S proteasome, an intensively studied protease, represents the sophisticated complex of subunits and is critical for life. This complex is implicated in the temporally controlled ATP‐dependent degradation of key regulatory proteins controlling main cellular processes (cell cycle, apoptosis, differentiation, development, immune response, malignant transformation), as well as in regulation of different stages of gene expression (Collins and Tansey, 2006, Ferdous et al., 2007, Glickman and Ciechanover, 2002, Kloetzel, 2004, Maupin‐Furlow et al., 2006, Pajonk and McBride, 2001, Reed, 2006, Sikder et al., 2006, Wojcik et al., 2000).

The participation of the proteasome‐ubiquitin pathway in the control of degradation of regulatory proteins involves not only the regulation of the complicated enzyme system of conjugation of the ubiquitin molecules to the substrates but also the highly complex control of the composition and the activities of the proteasome particle itself. These particles are heterogeneous due to subtypes synthesized from duplicated genes and/or alternative splicing, to posttranslational modifications and to association of 20S core with alternative regulatory complexes (Glickman and Raveh, 2005, Maupin‐Furlow et al., 2006). Here we will describe recent studies revealing the current knowledge about proteasomes involvement in the fundamental biological processes such as control of cell cycle, apoptosis, differentiation, modulation of immune responses, about their isoform complexity including subunits' posttranslational modifications, structural and functional responsiveness to cell requirements and participation of these particles in the main stages of gene expression.

Section snippets

The core particle, 19S regulatory particle, alternative regulatory particles

The 26S proteasome, further often named “the proteasome, ” is an ATP‐dependent multicatalytic enzyme complex found in the nucleus and cytoplasm not only of all eukaryotic cells, but also of Archebacteria and in some Eubacteria. Proteasomes are responsible for the degradation of most cellular proteins (Coux et al., 1994). The 26S proteasomes constitutes the central proteolytic machinery of the ubiquitin/proteasome system, and is composed of a core catalytic complex, called 20S proteasome, capped

Cell cycle control

The cell cycle in eukaryotes is regulated by consecutive activation of cyclin‐dependent kinases (CDKs) by various cyclins. Cyclins are synthesized during strongly defined moments of a cell cycle and, being the extremely unstable, exist and work only at the certain phases of the cell cycle and during the certain period of time. For example, cyclins D and E are active during phase G1; cyclins E and A, during phase S. Consecutive appearance and disappearance of the pairs cyclin‐CDK at various

Heterogeneity of proteasomes in the cell

The more in a complicated manner the organization of both the separate cells, and the entire organisms is, the more fancily becomes the main cellular machinery, aimed to non‐lysosomal protein cleavage. The structure and sub‐unit content of ancestral proteasome complex found in Prokaryota, both Archea (Maupin-Furlow and Ferry, 1995) and Eubacteria (Hu et al., 2006, Lupas et al., 1994, Tamura et al., 1995), is respectively simple: subunits are divided into only two types, α and β, forming four

Reprogramming of Proteasomes at Immune Response, Differentiation and Apoptosis

It was mentioned above that the proteasomes play important roles in most cellular processes. To perform their functions, proteasomes must be under a tight regulatory control and change their subunit composition and enzymatic activities to adapt them to the requirements of the each of the cellular processes during the cell life. Phosphorylation at serine, threonine, or tyrosine residues of regulatory proteins is the key event in signal transduction and cell cycle progression (Coux et al., 1996).

Action at multiple stages of transcription process

A growing body of evidence reveals that proteasomes are involved in the control of different levels of gene expression: transcription process, messenger RNA stability and translation.

The physical and functional association of subunits of the 20S core and 19S regulatory proteasome subparticles with approximately 6400 yeast genes has been studied (Sikder et al., 2006). The results revealed the cross‐linking of the intact 26S proteasomes to most genes, while several hundred genes interacted with

Concluding Remarks

Recent evidence show that proteasomes are involved in the control of the main cellular processes as well as in the main stages of gene expression and that these complexes themselves are subjected to tightly organized regulation. However, the cellular pathways of this regulation (enzymes responsible for modifications of subunits, control pathways of their activity, mechanisms of the regulation of subunit expression, of cellular localization and others) remain mainly uninvestigated.

Furthermore,

Acknowledgments

This work was supported by Russian Foundation for Basic Research (project No. 08‐04‐00834) and St. Petersburg's Scientific Center of Russian Academy of Sciences.

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