Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules
TL;DR: Peptide aldehydes that inhibit major peptidase activities of the 20S and 26S proteasomes are shown to reduce the degradation of protein and ubiquitinated protein substrates by 26S particles.
About: This article is published in Cell.The article was published on 1994-09-09. It has received 2503 citations till now. The article focuses on the topics: MHC class I & Antigen processing.
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TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
7,888 citations
TL;DR: The discovery of a STAT in Drosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins.
Abstract: STATs (signal transducers and activators of transcription) are a family of latent cytoplasmic proteins that are activated to participate in gene control when cells encounter various extracellular polypeptides. Biochemical and molecular genetic explorations have defined a single tyrosine phosphorylation site and, in a dimeric partner molecule, an Src homology 2 (SH2) phosphotyrosine-binding domain, a DNA interaction domain, and a number of protein-protein interaction domains (with receptors, other transcription factors, the transcription machinery, and perhaps a tyrosine phosphatase). Mouse genetics experiments have defined crucial roles for each known mammalian STAT. The discovery of a STAT in Drosophila , and most recently in Dictyostelium discoideum , implies an ancient evolutionary origin for this dual-function set of proteins.
3,860 citations
TL;DR: It is shown that ubiquitination of β‐catenin is greatly reduced in Wnt‐expressing cells, providing the first evidence that the ubiquitin–proteasome degradation pathway may act downstream of GSK3β in the regulation ofβ‐ catenin.
Abstract: beta-catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of beta-catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady-state level outside the cadherin-catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3beta (GSK3beta) phosphorylation consensus motif of beta-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in beta-catenin resembles a motif in IkappaB (inhibitor of NFkappaB) which is required for the phosphorylation-dependent degradation of IkappaB via the ubiquitin-proteasome pathway. We show that ubiquitination of beta-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin-proteasome degradation pathway may act downstream of GSK3beta in the regulation of beta-catenin.
2,432 citations
Cites background from "Inhibitors of the proteasome block ..."
...Upon treatment with ALLN, all three cell lines clearly showed activity of proteasomes (Rock et al., 1994)....
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...Upon treatment with ALLN, all three cell lines clearly showed activity of proteasomes (Rock et al., 1994)....
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TL;DR: Two β-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
Abstract: The crystal structure of the 20S proteasome from the yeast Saccharomyces cerevisiae shows that its 28 protein subunits are arranged as an (α1...α7, β1...β7)2 complex in four stacked rings and occupy unique locations. The interior of the particle, which harbours the active sites, is only accessible by some very narrow side entrances. The β-type subunits are synthesized as proproteins before being proteolytically processed for assembly into the particle. The proforms of three of the seven different β-type subunits, (β1/PRE3, β2/PUP1 and β5/PRE2, are cleaved between the threonine at position 1 and the last glycine of the pro-sequence, with release of the active-site residue Thr 1. These three β-type subunits have inhibitor-binding sites, indicating that PRE2 has a chymotrypsin-like and a trypsin-like activity and that PRE3 has peptidylglutamyl peptide hydrolytic specificity. Other β-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.
2,235 citations
TL;DR: The identification of an oxygen-dependent degradation (ODD) domain within HIF-1alpha that controls its degradation by the ubiquitin-proteasome pathway is reported and may provide a means of controlling gene expression by changes in oxygen tension.
Abstract: Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of α and β subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1α, which is otherwise rapidly degraded in oxygenated cells. We report the identification of an oxygen-dependent degradation (ODD) domain within HIF-1α that controls its degradation by the ubiquitin-proteasome pathway. The ODD domain consists of ≈200 amino acid residues, located in the central region of HIF-1α. Because portions of the domain independently confer degradation of HIF-1α, deletion of this entire region is required to give rise to a stable HIF-1α, capable of heterodimerization, DNA-binding, and transactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a stable protein, Gal4. Hence, the ODD domain plays a pivotal role for regulating HIF-1 activity and thereby may provide a means of controlling gene expression by changes in oxygen tension.
2,113 citations
References
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TL;DR: It is shown that murine lymphoma cells selected for loss of H–2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive.
Abstract: Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.
2,119 citations
TL;DR: Protein Degradation in Mammalian Tissues upon Deprivation of Nutrients and Mechanisms Regulating Protein Degradation and RNA Synthesis in E. coli are considered.
Abstract: PERSPECTIVES AND OVERVIEW . . . . . . . . . . . . . . . . . . 748 INTRODUCTION ....... 749 SELECTIVITY OF INTRACELLULAR PROTEIN DEGRADATION 749 Selectivity of the Degradative Process in Mammalian Cells 749 Biochemical Basis of Selectivity 752 Degradation of Abnormal Proteins in Mammalian Cells 755 Aging and the Degradation of Abnormal Proteins 758 Selectivity 0/ the Degradative Process in E. coli 760 Degradation of Abnormal Proteins in E. coli 762 E. coli MUlants De/ee/ive in Pro/ein Degradation 766 CONTROL OF THE OVERALL RATES OF PROTEIN DEGRADATION 767 Regulation of Proteolysis in E. coli 767 Mechanisms Regulating Protein Degradation and RNA Synthesis in E. coli 773 Regulation of Pratein Degradation in Mammalian Cells .. ....... ....... 775 Protein Degradation and Control of Cell Growth 776 Protein Degradation in Mammalian Tissues upon Deprivation of Nutrients 780 BIOCHEMICAL CONSIDERATIONS . . . .. ......... 783 Effects uf Inhibitors uf Protein Synthesis on Protein Degradation 783 Energy Requirement for Protein Degradation 787 The E nzymes Responsible lor Protein Degradation ........ ......... ........ 791
1,656 citations
TL;DR: The Ubiquitin-C-TERMINAL HYDROLASES study highlights the importance of knowing the carrier and removal status of these components in the preparation of the UBIQUITIN-MEDIATED DEGRADATION.
Abstract: PERSPECTIVES AND SUMMARy 762 INTRODUCTION 762 ENZYMES OF UBIQUITIN ACTIVATION AND LIGATION 764 Ubiq u it in -Activatin g En zyme, E } . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . 764 Ubiquitin-Carrier Proteins, E2s 767 Ubiq uit in -Protein Ligases, E3s.. ... ........ ... . ... . .... .. . 771 DEGRADATION OF PROTEINS LIGATED TO UBIQUITIN 775 The 26S Protease Complex and its Three Components 775 Identification of CF-3 as the 20S P rotea se Complex . . . . . . . . . . . . . . . . . .... . . . .. . .... . . . . . . . 777 P ossible Role s of ATP 780 UBIQUITIN-C-TERMINAL HYDROLASES 781 SIGNALS IN PROTEINS FOR UBIQUITIN-MEDIATED DEGRADATION 786 The N-Term ina l Recognition Signa l . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 786 Sign als t hat are Distinct from the N-Term in al Re sid ue .... . . ......... 790 DEGRADATION OF SPECIFIC CELLULAR PROTEINS BY THE UBIQUITIN SYSTEM: REGULATORY ASPECTS 792 P hytochrome . . . . .. . . . . . . . 792 Oncoprotein s. . ... . .... . . .... ....... . ..... .... ..... ..... . ... . ........ . ...... ......... . ... 794 MATaJ. Repre ssor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795 Cyclin s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796 DIVERSE FUNCTIONS OF UBIQUITIN CONJUGATION.. 799 CONCLUDING REMARKS 801
1,394 citations
"Inhibitors of the proteasome block ..." refers background in this paper
...It is essential in the ATP-ubiquitin-dependent pathway, where it functions as the proteolytic core of the 26S (1500 kDa) complex that degrades ubiquitin-conjugated proteins (Goldberg, 1992; Hershko and Ciechanover, 1992; Rechsteiner et al., 1993)....
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..., 1991), which contains additional subunits that allow the ATP-dependent degradation of ubiquitinoconjugated proteins (Goldberg, 1992; Hershko and Ciechanover, 1992; Rechsteiner et al,, 1993)....
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...Second, cell proteins with abnormal conformation, whose accumulation could be damaging, are degraded particularly rapidly (Goldberg and St. John, 1976; Rechsteiner, 1987; Hershko and Ciechanover, 1992)....
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...an extralysosomal pathway that is dependent on ATP (Goldberg and St. John, 1976; Hershko and Ciechanover, 1992); however, it is uncertain which protease(s) degrades the bulk of cell proteins....
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...In fact, one possible reason that the presentation of peptons has been detected may be that incomplete polypeptides resulting from mistakes in transcription or translation are preferentially degraded (Goldberg and St. John, 1976; Hershko and Ciechanover, 1992) and therefore might be especially effective in generating peptides for MHC class I presentation....
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TL;DR: C57BL/6 mice immunized against a syngeneic tumor cell transfected with chicken ovalbumin cDNA gave rise to H-2Kb-restricted CTL specific for the OVA258-276 peptide, which was able to target H- 2b cells for lysis by the CTL in a 3 hr assay.
1,124 citations
Additional excerpts
...cessing (Moore et al., 1988) and presentation on MHC...
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TL;DR: The importance of conformational changes accompanying peptide binding that affect subunit stability of MHC molecules, and the relationship between these changes and the handling of proteins by intracellular chaperones, are emphasized as key features in the operation of the class I and class II presentation pathways.
Abstract: T lymphocytes with alpha beta receptors recognize antigen in association with the polymorphic products of the class I and class II loci of the major histocompatibility complex (MHC). This presentation of antigen results from the intracellular generation of protein fragments, and the binding and transport to the cell surface of these peptides in stable association with the MHC class I and class II molecules. Each class of MHC molecule appears specialized for capture of peptides present in a particular intracellular compartment. We describe here the structural basis of peptide-MHC molecule interaction, the differences in biochemical behavior that focus the two classes of MHC molecules on peptides of distinct size and location, and the cell biology of MHC molecule transport, peptide generation, and intracellular movement. The importance of conformational changes accompanying peptide binding that affect subunit stability of MHC molecules, and the relationship between these changes and the handling of proteins by intracellular chaperones, are emphasized as key features in the operation of the class I and class II presentation pathways.
1,051 citations
"Inhibitors of the proteasome block ..." refers background in this paper
...Another important function of intracellular proteolysis is to generate the small peptides that are presented to T lymphocytes to initiate immune responses (Goldberg and Rock, 1992; Germain and Margulies, 1993)....
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...The roles of the lysosomal-endosomal proteases in MHC class II antigen presentation and in the degradation of endocytosed proteins has been established by the use of weak bases and inhibitors of the cysteine proteases of the lysosome (Germain and Margulies, 1993); however, these agents do not affect class I antigen presentation (Braciale et al....
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