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)

Until recently, the degradation of aberrant and unassembled proteins retained in the endoplasmic reticulum (ER) was thought to involve unidentified ER-localized proteases. We now show that the ER-associated degradation (ERAD) of two mutant proteins that accumulate in the ER lumen is inhibited in a proteasome-defective yeast strain and when cytosol from this mutant is used in an in vitro assay. In addition, ERAD is limited in vitro in the presence of the proteasome inhibitors, 3,4-dichloroisocoumarin and lactacystin. Furthermore, we find that an ERAD substrate is exported from ER-derived microsomes, and the accumulation of exported substrate is 2-fold greater when proteasome mutant cytosol is used in place of wild-type cytosol. We conclude that lumenal ERAD substrates are exported from the yeast ER to the cytoplasm for degradation by the proteasome complex.
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PMID:Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. 894 15

The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus gene US2 specifies a product capable of dislocating MHC class I molecules from the endoplasmic reticulum to the cytosol and delivering them to the proteasome. This process involves the Sec61 complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.
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PMID:Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. 894 60

Class I and II molecules of the major histocompatibility complex present peptides to T cells. Class I molecules bind peptides that have been generated in the cytosol by proteasomes and delivered into the endoplasmic reticulum by the transporter associated with antigen presentation. In contrast, class II molecules are very efficient in the presentation of antigens that have been internalized and processed in endosomal/lysosomal compartments. In addition, class II molecules can present some cytosolic antigens by a TAP-independent pathway. To test whether this endogenous class II presentation pathway was linked to proteasome-mediated degradation of antigen in the cytosol, the N-end rule was utilized to produce two forms of the influenza virus matrix protein with different in vivo half-lives (10 min vs. 5 h) when expressed in human B cells. Whereas class I molecules presented both the short- and the long-lived matrix proteins, class II molecules presented exclusively the long-lived form of antigen. Thus, rapid degradation of matrix protein in the cytosol precluded its presentation by class II molecules. These data suggest that the turnover of long-lived cytosolic proteins, some of which is mediated by delivery into endosomal/ lysosomal compartments, provides a mechanism for immune surveillance by CD4+ T cells.
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PMID:Presentation of a cytosolic antigen by major histocompatibility complex class II molecules requires a long-lived form of the antigen. 896 16

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced "herd"), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2, has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans sel-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the agents of HMG-R degradation but not the regulators of that degradation.
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PMID:Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. 897 Jan 63

Murine IL-2-activated, adherent natural killer (A-NK) cells produce proteolytic activities (including a chymase and a tryptase) which appear to be components of the proteasome/multicatalytic proteinase complex and appear to represent the mouse homologues of the rat A-NK cell A-NKP 2 and A-NKP 1 protease components. The chymase is readily inhibited by Z-Gly-Gly-Phe chloromethylketone (Z-GGF) and to a lesser extent by N-tosyl-L-phenylalanyl-chloromethylketone (TPCK). In addition, this activity is inhibited by 3,4-dichloroisocoumarin (DCI), a suicide inhibitor for both chymotryptic and tryptic proteolytic enzymes. Protease inhibitors reduced A-NK cell-mediated cytotoxicity against P815 target cells, most prominently with inhibitors of chymotryptic and tryptic enzymes, including TPCK, DCI and Z-GGF. A polyclonal rabbit antibody raised against rat liver proteasome immunofluorescently labeled the cytoplasm of 4-day-cultured murine A-NK cells, multiple granules in 5 to 6-day cultures and large intracytoplasmic pools in cells cultured longer. Ultrastructurally this shift in labeling over time corresponded to an immunogold redistribution to non-membrane delineated mucoid masses. A minor nuclear labeling was noted at all time points, whereas the cisternae of the endoplasmic reticulum or Golgi region were negative. It is concluded that murine A-NK cells synthesize and accumulate proteasome in large intracytoplasmic pools, non-delineated by membranes which can occupy up to 80% of the A-NK cellular volume. The potential function of the proteasome produced by A-NK cells including cell-mediated cytotoxicity against tumor target cells remains to be elucidated.
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PMID:Immunocytochemical localization of multicatalytic protease complex (proteasome) during generation of murine IL-2-activated natural killer (A-NK) cells. 898 Sep 12

We describe the effect of the proteasome specific inhibitor lactacystin on the metabolic stability of influenza nucleoprotein (NP) and on the generation of antigens presented by human and murine class I molecules of the major histocompatibility complex to cytotoxic T lymphocytes (CTL). We show that cells treated with lactacystin fail to present influenza antigens to influenza-specific CTL, but retain the capacity to present defined epitopes expressed as peptides intracellularly by recombinant vaccinia viruses. This block in antigen presentation can be overcome by expressing the viral protein within the lumen of the endoplasmic reticulum, confirming the specificity of lactacystin for cytosolic proteases. We also show that the effect of lactacystin on antigen presentation correlates with the block of breakdown of a rapidly degraded form of the influenza NP linked to ubiquitin. These results demonstrate that proteasome-dependent degradation plays an important role in the cytosolic generation of CTL epitopes.
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PMID:The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells. 902 37

MHC class I molecules present antigenic peptides that are mostly derived from endogenous cytosolic proteins. Recent studies addressing the function of the proteasome and its activator complexes have advanced our understanding of the cytosolic processing of peptides. Transporters associated with antigen processing (TAPs) translocate these peptides to the endoplasmic reticulum where MHC class I molecules, which are retained in transient complexes with chaperones and TAPs, await them for binding. The sequence specificity and the peptide length preference of TAPs roughly meet the requirements of class I molecules in a range of different species, suggesting evolutionary shaping of the specificity of TAPs.
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PMID:Generation, intracellular transport and loading of peptides associated with MHC class I molecules. 903 71

Human immunodeficiency virus (HIV) type 1 encodes three genes, Vpu, Env and Nef, that decrease cellular CD4. Vpu and Env act cooperatively to accelerate degradation of CD4 in the endoplasmic reticulum. Here we report that Vpu/Env-induced CD4 degradation is inhibited by lactacystin, a specific inhibitor of the proteasome, and by other proteasome inhibitors, but not by non-proteasome protease inhibitors. We also note that Vpu has amino acid sequence homology with a segment of IkappaB known to be involved in proteasome-mediated degradation, suggesting that HIV-1 could have transduced cellular sequences to enhance down-regulation of CD4.
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PMID:Rapid degradation of CD4 in cells expressing human immunodeficiency virus type 1 Env and Vpu is blocked by proteasome inhibitors. 904 13

N-acetyl-L-leucyl-L-leucyl-L-norleucinal (LLnL), which reversibly inhibits the proteasome in addition to other proteases, and a more specific irreversible inhibitor of the proteasome, lactacystin, were found to cause the accumulation of major histocompatibility complex (MHC) class I heavy chains in the cytosol of the beta2-microglobulin-deficient cell line Daudi and the TAP-deficient cell line .174. These cell lines, which are severely impaired in their ability to fold MHC class I heavy chain, showed an accumulation of soluble class I heavy chains at different rates over a period of hours in the presence of LLnL. The accumulation of soluble class I heavy chains in the presence of either LLnL or lactacystin was easily revealed in Daudi and .174 but almost undetectable in a Daudi transfectant expressing beta2-microglobulin and in 45.1, the wild-type parent of .174. The soluble class I heavy chain was also found to be devoid of its N-linked glycan and to be located in the cytosol. When the gene for ICP47, a herpes simplex virus protein that blocks the translocation of peptides into the endoplasmic reticulum, was transfected into 45.1, a similar accumulation of soluble MHC class I heavy chain was detectable. These data suggest that in cells where the MHC class I molecule is unable to assemble properly, the misfolded heavy chain is removed from the endoplasmic reticulum to the cytosol, deglycosylated, and degraded by the proteasome.
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PMID:Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. 905 Aug 76

Pathways for presenting proteins from the extracellular fluids on MHC class I molecules have been described in macrophages. However, it is uncertain whether similar mechanisms exist in dendritic cells, because conventional preparations of these cells can be contaminated with macrophages. We addressed this issue by transducing granulocyte-macrophage CSF into bone marrow cultures followed by supertransfection with myc and raf oncogenes. These immortalized clones displayed dendritic morphology, and many expressed the dendritic cell-specific markers DEC-205 and 33D1 as well as high levels of MHC molecules and costimulatory molecules. Using these cloned dendritic cells, we found that exogenous OVA could be presented on both their MHC class I and class II molecules. This presentation was markedly enhanced when the Ag was particulate and internalized by phagocytosis. Presentation of particulate OVA on MHC class I molecules was insensitive to the weak base chloroquine, but was blocked by peptide aldehyde inhibitors of the proteasome, indicating that the class I-presented peptides were generated in the cytosol. Brefeldin A, which inhibits the exocytosis of newly synthesized proteins from the endoplasmic reticulum, also inhibited Ag presentation. These results establish that dendritic cells can present exogenous Ags on MHC class I molecules and appear to use a similar phagosome to cytosol pathway as macrophages. Therefore, dendritic cells are likely to play an important role in generating immune responses to tissue transplants and tumors in vivo. Furthermore, these findings provide an approach for targeting vaccine Ags into these cells to prime immune responses in vivo.
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PMID:Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. 905 6


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