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)

PEX genes encode proteins (peroxins) that are required for the biogenesis of peroxisomes. One of these peroxins, Pex5p, is the receptor for matrix proteins with a type 1 peroxisomal targeting signal (PTS1), which shuttles newly synthesized proteins from the cytosol into the peroxisome matrix. We observed that in various Saccharomyces cerevisiae pex mutants disturbed in the early stages of PTS1 import, the steady-state levels of Pex5p are enhanced relative to wild type controls. Furthermore, we identified ubiquitinated forms of Pex5p in deletion mutants of those PEX genes that have been implicated in recycling of Pex5p from the peroxisomal membrane into the cytosol. Pex5p ubiquitination required the presence of the ubiquitin-conjugating enzyme Ubc4p and the peroxins that are required during early stages of PTS1 protein import. Finally, we provide evidence that the proteasome is involved in the turnover of Pex5p in wild type yeast cells, a process that requires Ubc4p and occurs at the peroxisomal membrane. Our data suggest that during receptor recycling a portion of Pex5p becomes ubiquitinated and degraded by the proteasome. We propose that this process represents a conserved quality control mechanism in peroxisome biogenesis.
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PMID:Ubiquitination of the peroxisomal targeting signal type 1 receptor, Pex5p, suggests the presence of a quality control mechanism during peroxisomal matrix protein import. 1553 88

Prolonged mechanical ventilation (MV) results in diaphragmatic atrophy due, in part, to an increase in proteolysis. These experiments tested the hypothesis that MV-induced diaphragmatic proteolysis is accompanied by increased expression of key components of the ubiquitin-proteasome pathway (UPP). To test this postulate, we investigated the effect of prolonged MV on UPP components and determined the trypsin-like and peptidylglutamyl peptide hydrolyzing activities of the 20S proteasome. Adult Sprague-Dawley rats were assigned to either control or 12-h MV groups (n=7/group). MV animals were anesthetized, tracheostomized, and ventilated with room air for 12 h. Animals in the control group were acutely anesthetized but not exposed to MV. Compared with controls, MV animals demonstrated increased diaphragmatic mRNA levels of two ubiquitin ligases, muscle atrophy F-box (+8.3-fold) and muscle ring finger 1 (+19.0-fold). However, MV did not alter mRNA levels of 14-kDa ubiquitin-conjugating enzyme, polyubiquitin, proteasome-activating complex PA28, or 20S alpha-subunit 7. Protein levels of 14-kDa ubiquitin-conjugating enzyme and proteasome-activating complex PA28 were not altered following MV, but 20S alpha-subunit 7 levels declined (-17.7%). MV increased diaphragmatic trypsin-like activity (+31%) but did not alter peptidylglutamyl peptide hydrolyzing activity. Finally, compared with controls, MV increased ubiquitin-protein conjugates in both the myofibrillar (+24.9%) and cytosolic (+54.7%) fractions of the diaphragm. These results are consistent with the hypothesis that prolonged MV increases diaphragmatic levels of key components within the UPP and that increases in 20S proteasome activity contribute to MV-induced diaphragmatic proteolysis and atrophy.
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PMID:Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm. 1555 10

Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.
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PMID:Strategies for suppressing muscle atrophy in chronic kidney disease: mechanisms activating distinct proteolytic systems. 1564 2

Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) on the reduction of body weight loss and protein degradation in the MAC16 model of cancer-induced weight loss has been compared with that of eicosapentaenoic acid (EPA), a recognized inhibitor of protein degradation. HMB was found to attenuate the development of weight loss at a dose greater than 0.125 g/kg accompanied by a small reduction in tumor growth rate. When EPA was used at a suboptimal dose level (0.6 g/kg) the combination with HMB seemed to enhance the anticachectic effect. Both treatments caused an increase in the wet weight of soleus muscle and a reduction in protein degradation, although there did not seem to be a synergistic effect of the combination. Proteasome activity, determined by the "chymotrypsin-like" enzyme activity, was attenuated by both HMB and EPA. Protein expression of the 20S alpha or beta subunits was reduced by at least 50%, as were the ATPase subunits MSS1 and p42 of the 19S proteasome regulatory subunit. This was accompanied by a reduction in the expression of E2(14k) ubiquitin-conjugating enzyme. The combination of EPA and HMB was at least as effective or more effective than either treatment alone. Attenuation of proteasome expression was reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB. In addition, HMB produced a significant stimulation of protein synthesis in skeletal muscle. These results suggest that HMB preserves lean body mass and attenuates protein degradation through down-regulation of the increased expression of key regulatory components of the ubiquitin-proteasome proteolytic pathway, together with stimulation of protein synthesis.
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PMID:Attenuation of proteasome-induced proteolysis in skeletal muscle by {beta}-hydroxy-{beta}-methylbutyrate in cancer-induced muscle loss. 1566 4

In the present study, the human TEB4 is identified as a novel ER (endoplasmic reticulum)-resident ubiquitin ligase. TEB4 has homologues in many species and has a number of remarkable properties. TEB4 contains a conserved RING (really interesting new gene) finger and 13 predicted transmembrane domains. The RING finger of TEB4 and its homologues is situated at the N-terminus and has the unconventional C4HC3 configuration. The N-terminus of TEB4 is located in the cytosol. We show that the isolated TEB4 RING domain catalyses ubiquitin ligation in vitro in a reaction that is ubiquitin Lys48-specific and involves UBC7 (ubiquitin-conjugating enzyme 7). These properties are reminiscent of E3 enzymes, which are involved in ER-associated protein degradation. TEB4 is an ER degradation substrate itself, promoting its own degradation in a RING finger- and proteasome-dependent manner.
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PMID:TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. 1567 84

Ubiquitin conjugation and in particular two distinct HECT ubiquitin ligases, Rsp5p and Tom1p, have been shown to participate in the regulation of mRNA export in Saccharomyces cerevisiae. The identification of the ubiquitin ligase substrates represents a major challenge in understanding how this modification may modulate mRNA export. Here, we identified Hpr1p, a member of the THO/TREX (transcription/export) complex that couples mRNA transcription to nuclear export as a target of the ubiquitin-proteasome pathway. Hpr1p degradation is enhanced at high temperature and appears linked to on-going RNA-polymeraseII-mediated transcription. Interestingly, the stability of the other THO complex components is not affected under these conditions indicating that Hpr1p turnover could control the formation of the THO/TREX complex and consequently mRNA export. Using in vivo and in vitro approaches we demonstrate that Rsp5p is responsible for the ubiquitylation of Hpr1p that also involves the ubiquitin-conjugating enzyme Ubc4p. Thus, Hpr1p represents the first nuclear export factor regulated by ubiquitylation, strongly suggesting that this post-translational modification participates in the coordination of transcription and mRNA export processes.
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PMID:The mRNA nuclear export factor Hpr1 is regulated by Rsp5-mediated ubiquitylation. 1571 80

Mutations in alpha-synuclein, Parkin, and UCH-L1 cause heritable forms of Parkinson disease. Unlike alpha-synuclein, for which no precise biochemical function has been elucidated, Parkin functions as a ubiquitin E3 ligase, and UCH-L1 is a deubiquitinating enzyme. The E3 ligase activity of Parkin in Parkinson disease is poorly understood and is further obscured by the fact that multiubiquitin chains can be formed through distinct types of linkages that regulate diverse cellular processes. For instance, ubiquitin lysine 48-linked multiubiquitin chains target substrates to the proteasome, whereas ubiquitin lysine 63-linked chains control ribosome function, protein sorting and trafficking, and endocytosis of membrane proteins. It is notable in this regard that ubiquitin lysine 63-linked chains promote the degradation of membrane proteins by the lysosome. Because both Parkin and alpha-synuclein can regulate the activity of the dopamine transporter, we investigated whether they influenced ubiquitin lysine 63-linked chain assembly. These studies revealed novel biochemical activities for both Parkin and alpha-synuclein. We determined that Parkin functions with UbcH13/Uev1a, a dimeric ubiquitin-conjugating enzyme, to assemble ubiquitin lysine 63-linked chains. Our results and the results of others indicate that Parkin can promote both lysine 48- and lysine 63-linked ubiquitin chains. alpha-Synuclein also stimulated the assembly of lysine 63-linked ubiquitin chains. Because UCH-L1, a ubiquitin hydrolase, was recently reported to form lysine 63-linked conjugates, it is evident that three proteins that are genetically linked to Parkinson disease can contribute to lysine 63 multiubiquitin chain formation.
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PMID:Alpha-synuclein and parkin contribute to the assembly of ubiquitin lysine 63-linked multiubiquitin chains. 1571 34

Muscle atrophy is a prominent feature of chronic kidney disease (CKD) and is frequent in other catabolic conditions. Results from animal models of these conditions as well as patients indicate that atrophy is mainly owing to accelerated muscle proteolysis in the ubiquitin-proteasome (Ub-P'some) proteolytic system. The Ub-P'some system, however, rapidly degrades actin or myosin but cannot breakdown actomyosin or myofibrils. Consequently, another protease must initially cleave the complex structure of muscle. We identified caspase-3 as an initial and potentially rate-limiting proteolytic step that cleaves actomyosin/myofibrils to produce substrates degraded by the Ub-P'some system. In rodent models of CKD and other catabolic conditions, we find that caspase-3 is activated and cleaves actomyosin to actin, myosin and their fragments. This initial proteolytic step in muscle leaves a characteristic footprint, a 14-kDa actin band, providing a potential diagnostic tool to detect muscle catabolism. We also found that stimulation of caspase-3 activity depends on inhibition of IRS-1-associated phosphatidylinositol 3-kinase (PI3K) activity; inhibiting PI3K in muscle cells also leads to expression of a critical E3-ubiquitin-conjugating enzyme involved in muscle protein breakdown: atrogin-1/MAFbx. Thus, protein breakdown by caspase-3 and the ubiquitin-proteasome system in muscle are stimulated by the same signal: a low PI3K activity. These responses could yield therapeutic strategies to block muscle atrophy.
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PMID:Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions. 1573 69

We reported previously that the human RNF2 (RING finger protein 2) protein is an E3 ubiquitin ligase that interacts with the human ubiquitin-conjugating enzyme Hip-2/hE2-25K. In the present study, we show that RNF2 interacts with S6' ATPase, a subunit of the proteasomal 19 S regulatory complex. S6' interacts with RNF2 through its N-terminal RING domain, and RNF2 interacts with S6' through its C-terminal region. Interestingly, the RNF2-S6' interaction increases the ATP hydrolysis activity of the S6' protein. Moreover, S6' ATPase activity is highly increased in the presence of ubiquitinated proteins. The present study suggests that the E3 ubiquitin ligase RNF2 might have a dual function: facilitating the ubiquitination of its target substrates and recruiting the substrates to the proteasome. Furthermore, ATP hydrolysis in the E3/proteasome complex might act as an important signal for the protein degradation pathway.
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PMID:E3 ubiquitin ligase RNF2 interacts with the S6' proteasomal ATPase subunit and increases the ATP hydrolysis activity of S6'. 1577 19

Selective protein degradation by the 26S proteasome requires the covalent attachment of several ubiquitin molecules in the form of a multiubiquitin chain. Ubiquitylation usually involves three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). However, in some cases, multiubiquitylation requires the additional activity of certain ubiquitin-chain elongation factors. Yeast UFD2 (ubiquitin fusion degradation), for example, binds to oligoubiquitylated substrates (proteins modified by only a few ubiquitin molecules) and catalyses multiubiquitin-chain assembly in collaboration with E1, E2 and E3. Enzymes possessing this specific activity have been proposed to be termed 'E4 enzymes'. Recent studies have provided accumulating evidence that has led some researchers in the field to conclude that E4, indeed, represents a distinct and novel class of enzymes.
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PMID:Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all. 1581 94


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