Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Turnover of damaged molecules is considered to play a key role in housekeeping of cells exposed to oxidative stress, and during the progress of ageing. In this work, global changes in the transcriptome were analysed during recovery of yeast cells after H(2)O(2) stress. Regarding induced genes, those associated with protein fate were the most significantly over-represented. In addition to genes encoding subunits of the 20S proteasome, genes related to vacuolar proteolysis (PEP4 and LAP4), protein sorting into the vacuole, and vacuolar fusion were found to be induced. The upregulation of PEP4 gene expression was associated with an increase in Pep4p activity. The induction of genes related to proteolysis was correlated with an increased protein turnover after H(2)O(2)-induced oxidation. Furthermore, protein degradation and the removal of oxidized proteins decreased in Pep4p-deficient cells. Pep4p activity also increased during chronological ageing, and cells lacking Pep4p displayed a shortened lifespan associated with higher levels of carbonylated proteins. PEP4 overexpression prevented the accumulation of oxidized proteins, but did not increase lifespan. These results indicate that Pep4p is important for protein turnover after oxidative damage; however, increased removal of oxidized proteins is not sufficient to enhance lifespan.
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PMID:The Pep4p vacuolar proteinase contributes to the turnover of oxidized proteins but PEP4 overexpression is not sufficient to increase chronological lifespan in Saccharomyces cerevisiae. 1715 12

The 20S proteasome is part of a larger complex, the 26S proteasome, that is implicated in the ATP-dependent degradation of multiubiquitin-conjugated proteins (1). About 80% of intracellular protein breakdown occurs via the ubiquitin-proteasome system (UPS). Key proteins such as transcription factors, nuclear receptors, cyclins, cyclin-dependent kinase inhibitors, p53, and NF-kappaB are regulated by this pathway. Thus, the UPS has been implicated to play a role in multiple cellular events including the cell cycle, signal transduction, antigen presentation, and DNA repair and transcription (2, 3). In 1984 Varshavsky and co-workers discovered that ubiquitin-dependent pathways play a role in cell cycle control, and suggested that protein degradation is instrumental in regulation of gene expression (4). Consistent with this idea, Franke and colleagues had shown that proteasomes localize to the nuclei of Xenopus laevis oocytes and HeLa cells (5, 6). Subsequent work confirmed that (i) all components of the UPS that are required for protein degradation indeed reside in the cell nucleus (7); (ii) nuclear proteins are substrates for proteasomal degradation (8); and (iii) proteasome-dependent proteolysis occurs in distinct nucleoplasmic foci (9). The intricate balance between nuclear function and quality control through proteolysis is exemplified by reports that show a correlation of aberrant nuclear protein aggregates with inhibition of transcription in neurodegenerative diseases such as Huntington's chorea and animal and cell culture models of polyglutamine repeat disorders (10,11).Considering the central role of the UPS in nuclear processes, a detailed knowledge of the time and place at which a substrate is ubiquitinylated and degraded will be essential to our understanding of the cellular mechanisms that orchestrate the expression of thousands of genes or development of subnuclear pathologies. Here, we describe fluorescence-based localization methods for proteasomes, protein aggregates, and proteasomal proteolysis in the cell nucleus that may aid to analyse the UPS in housekeeping and disease conditions.
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PMID:The nuclear ubiquitin-proteasome system: visualization of proteasomes, protein aggregates, and proteolysis in the cell nucleus. 1895 Nov 70

Cellular proteins and organelles such as peroxisomes are under continuous quality control. Upon synthesis in the cytosol, peroxisomal proteins are kept in an import-competent state by chaperones or specific proteins with an analogous function to prevent degradation by the ubiquitin-proteasome system. During protein translocation into the organelle, the peroxisomal targeting signal receptors (Pex5, Pex20) are also continuously undergoing quality control to enable efficient functioning of the translocon (RADAR pathway). Even upon maturation of peroxisomes, matrix enzymes and peroxisomal membranes remain subjected to quality control. As a result of their oxidative metabolism, peroxisomes are producers of reactive oxygen species (ROS), which may damage proteins and lipids. To counteract ROS-induced damage, yeast peroxisomes contain two important antioxidant enzymes: catalase and an organelle-specific peroxiredoxin. Additionally, a Lon-type protease has recently been identified in the peroxisomal matrix, which is capable of degrading nonfunctional proteins. Finally, cellular housekeeping processes keep track of the functioning of peroxisomes so that dysfunctional organelles can be quickly removed via selective autophagy (pexophagy). This review provides an overview of the major processes involved in quality control of yeast peroxisomes.
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PMID:Preserving organelle vitality: peroxisomal quality control mechanisms in yeast. 1953 6

INT6/EIF3E has been implicated in breast tumorigenesis, but its functional activities remain poorly defined. We found that, repressing INT6 expression induced transformed properties in normal human mammary epithelium (MCF10A); in contrast, Int6 silencing induced apoptosis in HeLa cells. As in fission yeast, Int6 in human cells was required for assembly of active proteasomes. A reverse-phase protein array screen identified SRC3/AIB1 as one oncoprotein the level and stability of which increased when Int6 was silenced in MCF10A cells. Our data further show that Int6 binds SRC3 and its ubiquitin ligase Fbw7, thus perhaps mediating the interaction between SRC3-Fbw7 and proteasomes. Consistent with this, Int6 silencing did not increase SRC3 levels in HeLa cells, which have low Fbw7 levels. It is surprising that, however, polyubiquitylated proteins do not accumulate or may even decrease in Int6-silenced cells that contain defective proteasomes. Considering that decreased ubiquitin might explain this observation and that Int6 might control ubiquitin levels in its role as a subunit of eIF3 (eukaryote translation initiation factor 3), we found that silencing Int6 reduced monoubiquitin protein levels, which correlated with a shift of ubiquitin mRNAs from larger polysomes to non-translating ribosomes. In contrast, levels of many housekeeping proteins did not change. This apparent reduction in the translation of ubiquitin genes correlated with a modest reduction in protein synthesis rate and formation of large polysomes. To further determine whether Int6 can selectively control translation, we analyzed translation of different 5'-untranslated region reporters and found that indeed, loss of Int6 had differential effects on these reporters. Together the data suggest that Int6 depletion blocks ubiquitin-dependent proteolysis by decreasing both ubiquitin levels and the assembly of functional proteasome machinery, leading to accumulation of oncoproteins, such as SRC3 that can transform mammary epithelium. Our data also raise the possibility that Int6 can further fine-tune protein levels by selectively controlling translation of specific mRNAs.
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PMID:Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium. 2089 Mar 3

The posttranslational addition of ubiquitin (Ub) helps control the half-life, localization, and action of many intracellular plant proteins. A primary function is the degradation of ubiquitylated proteins by the 26S proteasome, which in turn plays important housekeeping and regulatory roles by removing aberrant polypeptides and various normal short-lived regulators. Strikingly, both genetic and genomic studies reveal that Ub conjugation is extraordinarily complex in plants, with more than 1500 Ub-protein ligases (or E3s) possible that could direct the final transfer of the Ub moiety to an equally large number of targets. The cullin-RING ligases (CRLs) are a highly polymorphic E3 collection composed of a cullin backbone onto which binds carriers of activated Ub and a diverse assortment of adaptors that recruit appropriate substrates for ubiquitylation. Here, we review our current understanding of the organization and structure of CRLs in plants and their dynamics, substrates, potential functions, and evolution. The importance of CRLs is exemplified by their ability to serve as sensors of hormones and light; their essential participation in various signaling pathways; their control of the cell cycle, transcription, the stress response, self-incompatibility, and pathogen defense; and their dramatically divergent evolutionary histories in many plant lineages. Given both their organizational complexities and their critical influences, CRLs likely impact most, if not all, aspects of plant biology.
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PMID:The cullin-RING ubiquitin-protein ligases. 2137 Sep 76

Ischemia associated injury of the myocardium is caused by oxidative damage during reperfusion. Myocardial protection by ischemic preconditioning (IPC) was shown to be mediated by a transient 'iron-signal' that leads to the accumulation of apoferritin and sequestration of reactive iron released during the ischemia. Here we identified the source of this 'iron signal' and evaluated its role in the mechanisms of cardiac protection by hypoxic preconditioning. Rat hearts were retrogradely perfused and the effect of proteasomal and lysosomal protease inhibitors on ferritin levels were measured. The iron-signal was abolished, ferritin levels were not increased and cardiac protection was diminished by inhibition of the proteasome prior to IPC. Similarly, double amounts of ferritin and better recovery after ex vivo ischemia-and-reperfusion (I/R) were found in hearts from in vivo hypoxia pre-conditioned animals. IPC followed by normoxic perfusion for 30 min ('delay') prior to I/R caused a reduced ferritin accumulation at the end of the ischemia phase and reduced protection. Full restoration of the IPC-mediated cardiac protection was achieved by employing lysosomal inhibitors during the 'delay'. In conclusion, proteasomal protein degradation of iron-proteins causes the generation of the 'iron-signal' by IPC, ensuing de-novo apoferritin synthesis and thus, sequestering reactive iron. Lysosomal proteases are involved in subsequent ferritin breakdown as revealed by the use of specific pathway inhibitors during the 'delay'. We suggest that proteasomal iron-protein degradation is a stress response causing an expeditious cytosolic iron release thus, altering iron homeostasis to protect the myocardium during I/R, while lysosomal ferritin degradation is part of housekeeping iron homeostasis.
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PMID:Cardiac protection by preconditioning is generated via an iron-signal created by proteasomal degradation of iron proteins. 2315 31

The majority of peptides presented in MHC class I at the cell surface originate from the conventional antigen processing pathway, involving the proteasome and TAP peptide transporter. Alternative pathways, however, certainly contribute to the diversity of the total peptide repertoire. The importance of such TAP-independent processing pathways is nicely illustrated by the finding that individuals with an inherited deficiency in this peptide transporter still sufficiently mount T cell responses against viruses. Although defects in TAP do result in strongly decreased surface display of MHC class I molecules, the residual levels are capable to educate and elicit T cell immunity. In our work, we have shown that a broad repertoire of peptides is presented on processing-deficient cells. The characterization of these peptides, which we called TEIPP - "T-cell epitopes associated with impaired peptide processing", showed that they derive from housekeeping proteins, are diverse in length and amino-acid composition, and are not presented on normal cells. So, TAP-deficiency promotes the emergence of neo-antigens. These TAP-independent peptides might be processed via the two already known pathways, signal sequence liberation or furin-mediated cleavage in the Golgi, or via yet other routes. Our study on TEIPP antigens reveals that there is a world to be discovered in the alternative antigen processing field. Autophagy, vesicular routing, membrane-associated proteolysis, invariant chain involvement and recycling of MHC class I molecules all might come to the stage in this interesting research area.
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PMID:Importance of TAP-independent processing pathways. 2318 5

Autophagic turnover of intracellular constituents is critical for cellular housekeeping, nutrient recycling, and various aspects of growth and development in eukaryotes. Here we show that autophagy impacts the other major degradative route involving the ubiquitin-proteasome system by eliminating 26S proteasomes, a process we termed proteaphagy. Using Arabidopsis proteasomes tagged with GFP, we observed their deposition into vacuoles via a route requiring components of the autophagy machinery. This transport can be initiated separately by nitrogen starvation and chemical or genetic inhibition of the proteasome, implying distinct induction mechanisms. Proteasome inhibition stimulates comprehensive ubiquitylation of the complex, with the ensuing proteaphagy requiring the proteasome subunit RPN10, which can simultaneously bind both ATG8 and ubiquitin. Collectively, we propose that Arabidopsis RPN10 acts as a selective autophagy receptor that targets inactive 26S proteasomes by concurrent interactions with ubiquitylated proteasome subunits/targets and lipidated ATG8 lining the enveloping autophagic membranes.
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PMID:Autophagic Degradation of the 26S Proteasome Is Mediated by the Dual ATG8/Ubiquitin Receptor RPN10 in Arabidopsis. 2609 45

The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for "T-cell epitopes associated with impaired peptide processing." TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer's related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.
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PMID:Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome. 2609 83

Approximately two and a half percent of protein coding genes in Arabidopsis encode enzymes with known or putative proteolytic activity. Proteases possess not only common housekeeping functions by recycling nonfunctional proteins. By irreversibly cleaving other proteins, they regulate crucial developmental processes and control responses to environmental changes. Regulatory proteolysis is also indispensable in interactions between plants and their microbial pathogens. Proteolytic cleavage is simultaneously used both by plant cells, to recognize and inactivate invading pathogens, and by microbes, to overcome the immune system of the plant and successfully colonize host cells. In this review, we present available results on the group of proteases in the model plant Arabidopsis thaliana whose functions in microbial pathogenesis were confirmed. Pathogen-derived proteolytic factors are also discussed when they are involved in the cleavage of host metabolites. Considering the wealth of review papers available in the field of the ubiquitin-26S proteasome system results on the ubiquitin cascade are not presented. Arabidopsis and its pathogens are conferred with abundant sets of proteases. This review compiles a list of those that are apparently involved in an interaction between the plant and its pathogens, also presenting their molecular partners when available.
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PMID:Regulatory Proteolysis in Arabidopsis-Pathogen Interactions. 2640 38


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