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)

Molecular chaperones and the ubiquitin-proteasome pathway are known to participate in the quality control of proteins in cells. In this study, we examined the responses of small heat shock proteins to proteasome inhibitors to clarify their roles under conditions where misfolded proteins are abnormally accumulated. HSP27 and alphaB-crystallin accumulated in both soluble and, more prominently, insoluble fractions after exposure to MG-132, a proteasome inhibitor. Enhanced expression of mRNAs for HSP27 and alphaB-crystallin was observed, suggesting transcriptional activation. Phosphorylation of HSP27 and alphaB-crystallin in cells treated with MG-132 was enhanced concomitantly with activation of p38 and p44/42 MAP kinase pathways. Immunofluorescence analysis revealed that exposure to proteasome inhibitors induced the formation of aggresomes in U373 MG cells, to which HSP27 and alphaB-crystallin were recruited. However, phosphorylation was not required for this accumulation in aggresomes. Thus, HSP27 and alphaB-crystallin are increased, phosphorylated and localized in aggresomes when proteasome activity is inhibited.
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PMID:Inhibition of proteasomes induces accumulation, phosphorylation, and recruitment of HSP27 and alphaB-crystallin to aggresomes. 1192 98

The role of proteolytic enzymes in Shumiya cataract rats in alterations to lens proteins during cataract formation was studied immunohistochemically using antibodies against exopeptidases, such as lysosomal dipeptidyl peptidase II (DPP II), cytosolic dipeptidyl peptidase III, and soluble and membrane-bound alanyl aminopeptidases, and against cytosolic endopeptidases such as mu- and m-calpains, and 20S proteasome. AlphaB-crystallin was detected as a proteolytic marker in the lenses. A constant immunoreactivity against all the antibodies employed was observed in the lens epithelium independent of the strain and age of the rats. A weak immunoreactivity against exo- and endopeptidases and an intense reactivity against alphaB-crystallin were observed in the lens fibres of control rats at all ages. The immunoreactivity of these peptidases in lens fibres increased with age in cataract rats, but that of alphaB-crystallin decreased. No reactivity against exo- and endopeptidases was seen in the perinuclear region of lenses of control rats at all ages or in Shumiya cataract rats at 8 and 10 weeks of age, but an intense reactivity against these peptidases was observed in the lens perinuclear region of lenses in cataract rats at 12 and 14 weeks of age. AlphaB-crystallin immunoreactivity was observed with ordered striations in the lens perinuclear region of all control rats whereas the striations in this area of cataract rat lens were disorganized. Membrane-bound alanyl aminopeptidase was detected feebly in the lens epithelium and fibres of both types of rat at all weeks of age. These findings indicate that exo- and endopeptidases, except for membrane-bound alanyl aminopeptidase, are expressed intensively and are age-dependent. Conversely, the amount of alphaB-crystallin decreased with age in lens fibres of cataract rats. Calpains (mu- and m-), 20S proteasome, dipeptidyl peptidases II and III and soluble alanyl aminopeptidase are thought to induce lens opacification kinetically during cataract formation in Shumiya cataract rats through the intracellular turnover of lens proteins.
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PMID:Peptidases play an important role in cataractogenesis: an immunohistochemical study on lenses derived from Shumiya cataract rats. 1200 22

Alpha-crystallin, the major eye-lens protein with sequence homology with heat-shock proteins (HSPs), acts like a molecular chaperone by suppressing the aggregation of damaged crystallins and proteins. To gain more insight into its chaperoning ability, we used a protease as the model system that is known to require a propeptide (intramolecular chaperone) for its proper folding. The protease ("N" state) from Conidiobolus macrosporus (NCIM 1298) unfolds at pH 2.0 ("U" state) through a partially unfolded "I" state at pH 3.5 that undergoes transition to a molten globule-(MG) like "I(A)" state in the presence of 0.5 M sodium sulfate. The thermally-stressed I(A) state showed complete loss of structure and was prone to aggregation. Alpha-crystallin was able to bind to this state and suppress its aggregation, thereby preventing irreversible denaturation of the enzyme. The alpha-crystallin-bound I(A) state exhibited native-like secondary and tertiary structure showing the interaction of alpha-crystallin with the MG state of the protease. 8-Anilinonaphthalene sulphonate (ANS) binding studies revealed the involvement of hydrophobic interactions in the formation of the complex of alpha-crystallin and protease. Refolding of acid-denatured protease by dilution to pH 7.5 resulted in aggregation of the protein. Unfolding of the protease in the presence of alpha-crystallin and its subsequent refolding resulted in the generation of a near-native intermediate with partial secondary and tertiary structure. Our studies represent the first report of involvement of a molecular chaperone-like alpha-crystallin in the unfolding and refolding of a protease. Alpha-crystallin blocks the unfavorable pathways that lead to irreversible denaturation of the alkaline protease and keeps it in a near-native, folding-competent intermediate state.
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PMID:Alpha-crystallin binds to the aggregation-prone molten-globule state of alkaline protease: implications for preventing irreversible thermal denaturation. 1207 Mar 25

Alterations in peripheral myelin protein 22 (PMP22) gene expression are associated with demyelinating peripheral neuropathies. Overexpression of wild type (wt) PMP22 or inhibition of proteasomal degradation lead to the formation of aggresomes, intracellular ubiquitinated PMP22 aggregates. Aggresome formation has now been observed with two mutant PMP22s, the Tr- and TrJ-PMP22 when the proteasome is inhibited. The formation of these aggresomes required intact microtubules and involved the recruitment of chaperones, including Hsp40, Hsp70, and alphaB-crystallin. Spontaneously formed ubiquitinated PMP22 aggregates were also observed in Schwann cells of homozygous TrJ mice. Significant upregulation of both the ubiquitin-proteasomal and lysosomal pathways occurred in affected nerves suggesting that two pathways of PMP22 degradation are present. Thus, the presence of aggresomes appears to be a common finding in neuropathy models of PMP22 overexpression and of some point mutations known to cause neuropathy in mice and humans.
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PMID:Aggresome formation in neuropathy models based on peripheral myelin protein 22 mutations. 1212 49

The molecular events by which eccentric muscle contractions induce muscle damage and remodelling remain largely unknown. We assessed whether eccentric exercise modulates the expression of proteinases (calpains 1, 2 and 3, proteasome, cathepsin B+L), muscle structural proteins (alpha-sarcoglycan and desmin), and the expression of the heat shock proteins Hsp27 and alphaB-crystallin. Vastus lateralis muscle biopsies from twelve healthy male volunteers were obtained before, immediately after, and 1 and 14 days after a 30 min downhill treadmill running exercise. Eccentric exercise induced muscle damage as evidenced by the analysis of muscle pain and weakness, creatine kinase serum activity, myoglobinaemia and ultrastructural analysis of muscle biopsies. The calpain 3 mRNA level was decreased immediately after exercise whereas calpain 2 mRNA level was increased at day 1. Both mRNA levels returned to control values by day 14. By contrast, cathepsin B+L and proteasome enzyme activities were increased at day 14. The alpha-sarcoglycan protein level was decreased immediately after exercise and at day 1, whereas the desmin level peaked at day 14. alphaB-crystallin and Hsp27 protein levels were increased at days 1 and 14. Our results suggest that the differential expression of calpain 2 and 3 mRNA levels may be important in the process of exercise-induced muscle damage, whereas expression of alpha-sarcoglycan, desmin, alphaB-crystallin and Hsp27 may be essentially involved in the subsequent remodelling of myofibrillar structure. This remodelling response may limit the extent of muscle damage upon a subsequent mechanical stress.
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PMID:Molecular adaptations of neuromuscular disease-associated proteins in response to eccentric exercise in human skeletal muscle. 1218

Levels and phosphorylation states of the two small molecular chaperones, alphaB-crystallin and Hsp27, in disused rat soleus muscles were determined by Western blot analysis of extracts with antibodies recognizing each of the two proteins and their phosphorylated serine residues. Increased phosphorylation and relocalization to insoluble fractions were found within a few days of hind-limb suspension. High phosphorylation of alphaB-crystallin at Ser-59 (and to a certain extent, at Ser-45) and of Hsp27 at Ser-15 and Ser-85, along with phosphorylated, active states of p38 and p44/42 mitogen-activated protein kinases were maintained during hind-limb suspension but promptly returned to control levels within a 5-day recovery period. These results are similar to those observed with U373 MG glioma cells exposed to proteasome inhibitors (16). However, the responses of alphaB-crystallin and Hsp27 in suspended soleus muscles did not appear with ipsilateral transection of the sciatic nerve trunk, indicating mediation by nerve activity. The fact that ubiquitinated proteins accumulated in the insoluble fractions of suspended soleus muscle further suggests participation of alphaB-crystallin and Hsp27 in quality control of proteins in disused soleus muscle, with involvement of nerve activity-dependent processes.
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PMID:Innervation-dependent phosphorylation and accumulation of alphaB-crystallin and Hsp27 as insoluble complexes in disused muscle. 1220 38

AlphaB-crystallin is a small heat-shock protein in which three serine residues (positions 19, 45, and 59) can be phosphorylated under various conditions. We describe here the interaction of alphaB-crystallin with FBX4, an F-box-containing protein that is a component of the ubiquitin-protein isopeptide ligase SCF (SKP1/CUL1/F-box). The interaction with FBX4 was enhanced by mimicking phosphorylation of alphaB-crystallin at both Ser-19 and Ser-45 (S19D/S45D), but not at other combinations. Ser-19 and Ser-45 are preferentially phosphorylated during the mitotic phase of the cell cycle. Also alphaB-crystallin R120G, a mutant found to co-segregate with a desmin-related myopathy, displayed increased interaction with FBX4. Both alphaB-crystallin S19D/S45D and R120G specifically translocated FBX4 to the detergent-insoluble fraction and stimulated the ubiquitination of one or a few yet unknown proteins. These findings implicate the involvement of alphaB-crystallin in the ubiquitin/proteasome pathway in a phosphorylation- and cell cycle-dependent manner and may provide new insights into the alphaB-crystallin-induced aggregation in desmin-related myopathy.
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PMID:The small heat-shock protein alpha B-crystallin promotes FBX4-dependent ubiquitination. 1246 32

Tau-positive inclusions in oligodendrocytes are consistent neuropathological features of corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementias with Parkinsonism linked to chromosome 17. Here we show by immunohistochemistry that tau-positive oligodendroglial inclusion bodies also contain the small heat-shock protein (HSP) alphaB-crystallin but not HSP70. To study the molecular mechanisms underlying inclusion body formation, we engineered an oligodendroglia cell line (OLN-t40) to overexpress the longest human tau isoform. Treatment of OLN-t40 cells with okadaic acid (OA), an inhibitor of protein phosphatase 2A, caused tau hyperphosphorylation and a decrease in the binding of tau to microtubules. Simultaneously, tau-positive aggregates that also stained with the amyloid-binding dye thioflavin-S as well as with antibodies to tau and alphaB-crystallin were detected. However, they were only transiently expressed and were degraded within 24 hr. When the proteasomal apparatus was inhibited by carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG-132) after OA treatment, the aggregates were stabilized and were still detectable after 18 hr in the absence of OA. Incubation with MG-132 alone inhibited tau proteolysis and led to the induction of HSPs, including alphaB-crystallin and to its translocation to the perinuclear region, but did not induce the formation of thioflavin-S-positive aggregates. Hence, although tau hyperphosphorylation induced by protein phosphatase inhibition contributes to pathological aggregate formation, only hyperphosporylation of tau followed by proteasome inhibition leads to stable fibrillary deposits of tau similar to those observed in neurodegenerative diseases.
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PMID:Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid. 1452 89

The mechanism of small heat shock protein/alphaB-crystallin gene expression by proteasome inhibition was investigated. Expression of alphaB-crystallin was induced efficiently only by proteasome inhibition and not by heat shock while expression of HSP27 was induced efficiently by both proteasome inhibition and heat shock. The promoter of the alphaB-crystallin gene contains two conserved heat shock elements, one located between -397 and -374 and the other between -57 and -37, relative to the transcription start site. Electrophoretic mobility shift assay (EMSA) revealed that proteasome inhibition induces binding of heat shock factors to both heat shock elements in the alphaB-crystallin gene promoter. However, a transient transfection assay using deletion constructs of the alphaB-crystallin gene promoter showed that the region between -373 and -58 plays an important role in promoter activity. These results indicate the presence of differential response mechanisms of alphaB-crystallin gene expression to proteasome inhibition and heat shock, and that the activation of heat shock elements is not sufficient for the efficient induction of the alphaB-crystallin gene by proteasome inhibition.
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PMID:The mechanism of alphaB-crystallin gene expression by proteasome inhibition. 1457 8

Protein aggregates are oligomeric complexes of misfolded proteins, and serve as the seeds of inclusion bodies termed aggresomes in the cells. Heat shock proteins (Hsps) prevent misfolding and aggregate formation. Here, we found that only avian Hsp25 dominantly accumulated in the aggresomes induced by proteasome inhibition. Molecular cloning of chicken Hsp25 (cHsp25) revealed that it belongs to the Hsp30 family, which is a subfamily of the alpha-crystallin/small Hsp gene family. Unexpectedly, overexpression of cHsp25 into HeLa cells promoted inclusion formation whereas overexpression of mouse Hsp27 and its chicken homologue did not. These results suggest that cHsp25 acts differently from other small Hsps on protein aggregates.
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PMID:Hsp25, a member of the Hsp30 family, promotes inclusion formation in response to stress. 1513 47


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