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)

Ionizing radiation shares with cytokines, such as TNF-alpha, an ability to generate free radicals in cells and activate downstream proinflammatory responses through NF-kappaB-dependent signal transduction pathways. Support for the role of free radicals in triggering such responses comes from the use of free radical scavengers like N-acetyl-L-cysteine (NAC). The nature of the link between free radical generation and NF-kappaB activation is, however, unclear. In this study, we explore the possibility that scavenging of free radicals by NAC might not be the mechanism by which it inhibits NF-kappaB activation, but rather that NAC acts through inhibition of proteasome function. The effect of NAC on the chymotryptic function of the 26s and 20s proteasome complex was measured in extracts from EVC 304 bladder carcinoma cells by assessing degradation of fluorogenic substrates. NAC inhibited 26s but not 20s proteasome activity, suggesting that it interferes with 19s regulatory subunit function. NAC blocked radiation-induced NF-kappaB activity in ECV 304 cells and RAW 264.7 macrophages, as measured by a gel shift assay, at doses that inhibited proteasome activity. This provides a possible mechanism whereby NAC could block NF-kappaB activation and affect the expression of other molecules that are dependent on the ubiquitin/proteasome system for their degradation, other than by scavenging free radicals.
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PMID:N-acetyl-L-cysteine inhibits 26S proteasome function: implications for effects on NF-kappaB activation. 1195 54

A cytoplasmic peptide:N-glycanase has been implicated in the proteasomal degradation of newly synthesized misfolded glycoproteins exported from the endoplasmic reticulum. The gene encoding this enzyme (Png1p) has been identified in yeast. Based on sequence analysis, Png1p was classified as a member of the 'transglutaminase-like superfamily' that contains a putative catalytic triad of amino acids (cysteine, histidine, and aspartic acid). More recent studies in yeast indicate that Png1p can bind to the 26S proteasome through its interaction with the DNA repair protein Rad23p. A mouse homologue of Png1p (mPng1p) bound not only to the Rad23 protein, but also to various proteins related to ubiquitin and/or the proteasome through an extended amino-terminal domain. This NH2 terminus of mPng1p, which is not found in yeast, contains a PUB domain predicted to be involved in the ubiquitin-related pathway. This review will focus on the primary structure and potential functions of the cytoplasmic PNGases.
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PMID:Cytoplasmic peptide:N-glycanase (PNGase) in eukaryotic cells: occurrence, primary structure, and potential functions. 1197 27

Human herpesvirus 8 (HHV8) downregulates major histocompatibility complex (MHC) class I complexes from the plasma membrane via two of its genes, K3 and K5. The N termini of K3 and K5 contain a plant homeodomain (PHD) predicted to be structurally similar to RING domains found in E3 ubiquitin ligases. In view of the importance of the ubiquitin-proteasome system in sorting within the endocytic pathway, we analyzed its role in downregulation of MHC class I complexes in cells expressing K3. Proteasome inhibitors as well as cysteine and aspartyl protease inhibitors stabilize MHC class I complexes in cells expressing K3. However, proteasome inhibitors differentially affect sorting of MHC class I complexes within the endocytic pathway and prevent their delivery to a dense endosomal compartment. In this compartment, the cytoplasmic tail of MHC class I complexes is cleaved by cysteine proteases. The complex is then cleaved within the plane of the membrane by an aspartyl protease, resulting in a soluble MHC class I fragment composed of the lumenal domain of the heavy chain, beta(2)-microglobulin (beta(2)m), and peptide. We conclude that K3 not only directs internalization, but also targets MHC class I complexes to a dense endocytic compartment on the way to lysosomes in a ubiquitin-proteasome-dependent manner.
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PMID:Kaposi's sarcoma-associated herpesvirus K3 utilizes the ubiquitin-proteasome system in routing class major histocompatibility complexes to late endocytic compartments. 1199 80

Regulated proteolysis plays important roles in cell physiology as well as in pathological conditions. In most of the cases, regulated proteolysis is carried out by the ubiquitin- and proteasome-dependent proteolytic system, which is also in charge of the bulk of cytoplasmic proteolysis. However, apoptosis or the process of programmed cell death is regulated by a different proteolytic system, i.e. by caspases, a family of specialized cysteine proteases. Nevertheless, there is plenty of evidence of a crosstalk between the apoptotic pathways and the ubiquitin and proteasome system, whose function in apoptosis appears to be very complex. Proteasome inhibitors induce apoptosis in multiple cell types, while in other they are relatively harmless or even prevent apoptosis induced by other stimuli. Proteasomes degrade specific proteins during apoptosis, but on the other hand some components of the proteasome system are degraded by caspases. The knowledge about the involvement of the ubiquitin- and proteasome-dependent system in apoptosis is already clinically exploited, since proteasome inhibitors are being tested as experimental drugs in the treatment of cancer and other pathological conditions, where manipulation of apoptosis is desirable.
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PMID:Regulation of apoptosis by the ubiquitin and proteasome pathway. 1200 67

O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein that removes alkyl groups from DNA by transferring them to an internal Cys-145 residue. As the S-alkylcysteine is not converted back to cysteine, the protein can only act once and the resulting alkylated AGT molecule is rapidly degraded. The mechanism underlying the disappearance of the alkylated AGT has been studied in vivo in CHO cells and in vitro in reticulocyte lysates by using the pseudosubstrate O(6)-benzylguanine (BG) and mutant forms of AGT. The wild-type AGT was stable but was ubiquitinated and degraded rapidly by the proteasome after treatment with BG or with an oligodeoxyribonucleotide, which contained O(6)-methylguanine. Mutants C145F (and other mutants with bulky substituents at position 145), which have alterations that cause a steric alteration at the active site and also prevent hydrogen bonding involving Cys-145 resembled the alkylated AGT and were ubiquitinated and degraded rapidly irrespective of treatment with BG. Mutant M134F, which causes a steric alteration without interfering directly with the hydrogen-bonding network involving Cys-145, partially destabilized AGT and its degradation was increased further by reaction with BG. Mutant C145S, which maintains the hydrogen-binding network and causes no distortion, was not rapidly degraded. The results indicate that the conformational change resulting in the opening of the asparagine hinge region in the structure, which is brought about by formation of an S-alkyl adduct, leads to an increased recognition by a ubiquitin ligase targeting the protein for degradation. This is a novel type of post-translational modification causing ubiquitination.
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PMID:Degradation of the alkylated form of the DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase. 1201 56

Resistance to leishmanial infections depends on intracellular parasite killing by activated host macrophages through the L-arginine-nitric oxide (NO) metabolic pathway. Here we investigate the cell death process induced by NO for the intracellular protozoan Leishmania amazonensis. Exposure of amastigotes to moderate concentrations of NO-donating compounds (acidified sodium nitrite NaNO(2) or nitrosylated albumin) or to endogenous NO produced by lipopolysaccharide or gamma interferon treatment of infected macrophages resulted in a dramatic time-dependent cell death. The combined use of several standard DNA status analysis techniques (including electrophoresis ladder banding patterns, YOPRO-1 staining in flow cytofluorometry, and in situ recognition of DNA strand breaks by TUNEL [terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling] assay) revealed a rapid and extensive fragmentation of nuclear DNA in both axenic and intracellular NO-treated amastigotes of L. amazonensis. Despite some similarities to apoptosis, the nuclease activation responsible for characteristic DNA degradation was not under the control of caspase activity as indicated by the lack of involvement of cell-permeable inhibitors of caspases and cysteine proteases. In contrast, exposure of NO-treated amastigotes with specific proteasome inhibitors, such as lactacystin or calpain inhibitor I, markedly reduced the induction of the NO-mediated apoptosis-like process. These data strongly suggest that NO-induced oligonucleosomal DNA fragmentation in Leishmania amastigotes is, at least in part, regulated by noncaspase proteases of the proteasome. The determination of biochemical pathways leading up to cell death might ultimately allow the identification of new therapeutic targets.
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PMID:Nitric oxide-mediated proteasome-dependent oligonucleosomal DNA fragmentation in Leishmania amazonensis amastigotes. 1206 15

Inhibitor of apoptosis proteins (IAPs) can block apoptosis through interactions with members of the caspase family of cysteine proteases. Recent developments suggest that ubiquitin-proteasome mediated destruction of the Drosophila IAP, DIAP1, is a key event during the initiation of programmed cell death in the fly.
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PMID:Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. 1211 Jan 75

Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas Disease, contains cysteine, serine, threonine and metallo proteinases. Aspartic proteinases have not been found so far. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a complex mixture of isoforms by the major developmental stages of the parasite, including some membrane-bound isoforms. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus making the enzyme a very promising target for the development of new drugs against Chagas disease. In addition 30 kDa cathepsin B-like enzymes have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca(2+)-signalling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a serine carboxypeptidase belonging to the S10 family. Metalloproteinases homologous to the gp63 of Leishmania spp. are also present. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite.
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PMID:Proteinases of Trypanosoma cruzi: patential targets for the chemotherapy of Changas desease. 1217 84

The androgen receptor (AR) N-terminal domain plays a critical role in androgen-responsive gene regulation. A novel AR N-terminal-interacting protein (ARNIP) was isolated using the yeast two-hybrid system and its interaction with amino acids 11-172 of the normal or corresponding region of the polyglutamine-expanded human AR confirmed by glutathione S-transferase pulldown assays. ARNIP cDNAs cloned from NSC-34 (mouse neuroblastoma/spinal cord) or PC-3 (human prostate adenocarcinoma) mRNA encoded highly homologous 30 kDa (261 amino acids) cysteine-rich proteins with a RING-H2 (C3H2C3 zinc finger) domain; this motif is highly conserved in predicted ARNIP-homologous proteins from several other species. Expression of the approximately 1.7 kb ARNIP mRNA was detected in various tissues by Northern blotting, but was highest in mouse testes, kidney and several neuronal cell lines. In addition, the human ARNIP protein was found to be encoded by nine exons spanning 32 kb on chromosome 4q21. In COS-1 cells, coexpression of ARNIP and AR did not affect AR ligand-binding kinetics, nor did ARNIP act as a coactivator or corepressor in transactivation assays. However, AR N-terminal:C-terminal interaction was reduced in the presence of ARNIP. Intriguingly, ARNIP, and in particular its RING-H2 domain, functioned as a ubiquitin-protein ligase in vitro in the presence of a specific ubiquitin-conjugating enzyme, Ubc4-1. Mutation of a single cysteine residue in the ARNIP RING-H2 domain (Cys145Ala) abolished this E3 ubiquitin ligase activity. Fluorescent protein tagging studies revealed that AR-ARNIP interaction was hormone-independent in COS-1 cells, and suggest that colocalization of both AR and ARNIP to the nucleus upon androgen addition may allow ARNIP to play a role in nuclear processes. Thus, identification of a novel AR-interacting protein with ubiquitin ligase activity will stimulate further investigation into the role of ubiquitination and the ubiquitin-proteasome system in AR-mediated cellular functions.
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PMID:Cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity. 1220 Feb 28

The 26S proteasome is responsible for most intracellular proteolysis in eukaryotes. Efficient substrate recognition relies on conjugation of substrates with multiple ubiquitin molecules and recognition of the polyubiquitin moiety by the 19S regulatory complex--a multisubunit assembly that is bound to either end of the cylindrical 20S proteasome core. Only unfolded proteins can pass through narrow axial channels into the central proteolytic chamber of the 20S core, so the attached polyubiquitin chain must be released to allow full translocation of the substrate polypeptide. Whereas unfolding is rate-limiting for the degradation of some substrates and appears to involve chaperone-like activities associated with the proteasome, the importance and mechanism of degradation-associated deubiquitination has remained unclear. Here we report that the POH1 (also known as Rpn11 in yeast) subunit of the 19S complex is responsible for substrate deubiquitination during proteasomal degradation. The inability to remove ubiquitin can be rate-limiting for degradation in vitro and is lethal to yeast. Unlike all other known deubiquitinating enzymes (DUBs) that are cysteine proteases, POH1 appears to be a Zn(2+)-dependent protease.
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PMID:A cryptic protease couples deubiquitination and degradation by the proteasome. 1235 19


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