Chapter category: Cell Metabolism
The Ubiquitin-Proteasome Pathway in Mammals: Mechanisms of Action and Involvement in Pathogenesis of Human Diseases
Proteasomes: The World of Regulatory Proteolysis
Edited by: Wolfgang HiltISBN: 1-58706-011-6
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Chapter authors:
Aaron Ciechanover, Amir Orian and Alan L. Schwartz
Ubiquitin modification of a variety of cellular proteins plays a major role in numerous basic cellular processes. Among these are regulation of cell cycle and division, differentiation and development, involvement in the cellular response to stress and extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels and the secretory pathway, DNA repair, regulation of the immune and inflammatory responses and biogenesis of organelles. The mechanisms that underlie these complex processes are poorly understood and many of the target proteins have yet to be identified. In most cases, modification of the protein substrate by ubiquitin targets it for degradation by the 26S proteasome complex. In some cases however, modification leads to targeting of the protein for degradation in the lysosome or the vacuole. Nonproteolytic functions of ubiquitination have been proposed but never established firmly. The list of cellular proteins that are targeted by the ubiquitin system is growing exponentially. Among them are cell cycle regulators such as mitotic and G1 cyclins, and cyclin-dependent kinases and their inhibitors. Tumor suppressors such as p53, transcriptional activators and their inhibitors, fos, myc, NFkB and Ikba, for example, cell surface receptors such as the growth hormone receptor and the T cell receptor, and endoplasmic reticulum (ER) proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR), are also targeted by the ubiquitin system. Abnormal and otherwise denatured/misfolded proteins are recognized specifically and removed efficiently by the system. Degradation of a protein via the ubiquitin-proteasome pathway involves two discrete and successive steps:
- covalent attachment of multiple ubiquitin molecules to the protein substrate, and
- degradation of the tagged protein by the 26S proteasome, or in certain cases, by the lysosomes/vacuole (for selected recent reviews on the ubiquitin system, see refs. 1-18).
Additional chapters from this book:
Subunit Arrangement in the Human Proteasome
Burkhardt Dahlmann, Klavs B. Hendil, Poul Kristensen, Wolfgang Uerkvitz, Axel Sobek and Friedrich Kopp
The cytoplasm of mammalian tissues contains high concentrations of 20S proteasomes, the core of the major cytosolic proteolytic system.1 This multicatalytic proteinase degrades prot...
Active Sites and Assembly of the 20S Proteasome
Wolfgang Heinemeyer
During the past decade, rapid progress was made in elucidating the 20S proteasomes structure, as well as in establishing its unusual proteolytic mechanism. This was enormously facilitated by t...
The Regulatory Particle of the Yeast Proteasome
Michael H. Glickman, David M. Rubin, Christopher N. Larsen, Marion Schmidt and Daniel Finley
The ubiquitin-proteasome pathway is a major mediator of posttranslational control in eukaryotes, which functions in the control of cell proliferation, the cell cycle, and other processes. Conj...
Proteasome Crystal Structures
Matthias Bochtler, Lars Ditzel, Daniela Stock, Jan Löwe, Claudia Hartmann, Anja Dorowski, Robert Huber and Michael Groll
Many cellular processes, including stress response, cell cycle control and metabolic adaptation require protein turnover. The diversity of proteins that have to be degraded contrasts with the ...
The Mammalian Regulatory Complex of the 26 S Proteasome
Carlos Gorbea and Martin Rechsteiner
It has been nearly two decades since Hershko and colleagues elucidated the pathway that conjugates ubiquitin (Ub) to intracellular proteins and selects them for destruction.1-4 A se...
The 20S Proteasome Activator PA28 or 11S Regulator
Wolfgang Dubiel and Peter Kloetzel
The best characterized endogenous activators of the 20S proteasome are the PA700 or 19S regulator and the PA28 or 11S regulator (11S REG). The 19S regulator forms the 26S proteasome by associa...
Proteasome Activators and Synthetic Modulators: Significance for Antigen Presentation
Sherwin Wilk, Wei-Er Chen, Cezary Wojcik and Ronald P. Magnusson
Although the 20S proteasome is responsible for the bulk of extralysosomal proteolysis, the purified enzyme has negligible activity toward native proteins and only poorly degrades oligopeptides...
The Proteasome Inhibitors and Their Uses
Do Hee Lee and Alfred L. Goldberg
Knowledge about physiological functions of the proteasome, its biochemical mechanisms, and its importance in cell regulation have developed rather slowly, in large part because of difficulties...
Primary Destruction Signals
Erwin Knecht and A. Jennifer Rivett
Proteins that are relatively metabolically stable, with half-lives often exceeding the generation time coexist in the same cell with short-lived proteins that are rapidly degraded. The turnove...
The Ubiquitin System in Yeast
Erwin Knecht and A. Jennifer Rivett
For several years, most of the publications in the ubiquitin field began by accentuating the evolutionary conservation of the basic unit of the system, the polypeptide ubiquitin (Ub): ubiquiti...
The Ubiquitin-Proteasome Pathway in Mammals: Mechanisms of Action and Involvement in Pathogenesis of Human Diseases
Aaron Ciechanover, Amir Orian and Alan L. Schwartz
Ubiquitin modification of a variety of cellular proteins plays a major role in numerous basic cellular processes. Among these are regulation of cell cycle and division, differentiation and ...
Deubiquitinating Enzymes and the Regulation of Proteolysis
Rohan T. Baker
Ubiquitin is a highly conserved eukaryotic protein that is synthesized as a fusion protein precursor, either to itself, or to one of two ribosomal proteins.1 Accordingly, an endopep...
Degradation of Ornithine Decarboxylase, a Ubiquitin-Independent Proteasomal Process
Philip Coffino
Posttranslational control of the enzyme ornithine decarboxylase (ODC) employs unusual mechanisms. The proteasome degrades ODC, but ubiquitin is not involved in this process. ODC degradation is...
The Ubiquitin-Proteasome System in Cell Cycle Control
Carl Mann and Wolfgang Hilt
The duplication and division of cells occurs through a precisely regulated series of morphological and mechanistic steps. This process, termed the cell-division cycle, ...
p53 and the Proteasome Pathway
Martin Scheffner
In agreement with the notion that selective protein degradation is involved in the regulation of many cell regulatory processes, there is increasing evidence that deregulation of degradation c...
The Role of the Proteasome in Apoptosis
Lisa M. Grimm and Barbara A. Osborne
The regulated death of a cell is important in a variety of biological situations. Cell death is utilized in the selection of immunologically competent T- and B-lymphocytes, in the sculpting or...
Function of the Proteasome in the Protein Quality Control Process
Richard K. Plemper and Dieter H. Wolf
Secretion of proteins is an essential mechanism for life. Eukaryotic cells developed the complex central vacuolar system build up by the endoplasmic reticulum (ER), the Golgi apparatus, endoso...
MHC Class I Antigen Presentation and the Proteasome Pathway
Peter-M. Kloetzel and Ulrike Kuckelkorn
As part of the vertebrate immune surveillance system T cells recognize foreign (nonself) antigens which are bound by major histocompatibility complex (MHC) proteins. To allow binding to MHC mo...
Proteasomes in Prokaryotes
Peter Zwickl, Alfred L. Goldberg and Wolfgang Baumeister
The proteasome was first discovered as a cylinder-shaped particle of unknown function on electron micrographs of human erythrocyte cell lysates.1 More than a decade later, a large m...
The Proteasome in Posttranscriptional Control: A Protease with Endonuclease Activity?
Franck Petit, Claudia Kreutzer-Schmid, Karine Gautier, Anne-Sophie Jarrousse, Saloua Badaoui and Hans-Peter Schmid
Gene expression is regulated at different levels: transcription, translation and posttranslation (Fig. 1).
Cells use different modes of translational control1,2
Ubiquitin, Proteasomes and Neurodegenerative Disease
Peter-M. Kloetzel and Ulrike Kuckelkorn
While changing money in a bank at Wildbad-Kreut in Bavaria, Germany, in 1990 at a conference on "Proteolysis", one of us (RJM) observed in a pension pamphlet that nearly 40% of the G...
Proteasomes: A Historical Retrospective
Dieter H. Wolf
Proteasomes, the world of regulatory proteolysis: surprise and astonishment has struck the scientific community when the structural complexity and principal functions of these large proteinase...
