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)

Most cases of cystic fibrosis are caused by mutations that interfere with the biosynthetic folding of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to the rapid degradation of CFTR molecules that have not matured beyond the endoplasmic reticulum (ER). The mechanism by which integral membrane proteins including CFTR are recognized and targeted for ER degradation and the proteolytic machinery involved in this process are not well understood. We show here that the degradation of both wild-type and mutant CFTR is inhibited by two potent proteasome inhibitors that induce the accumulation of polyubiquitinated forms of immature CFTR. CFTR degradation was also inhibited by coexpression of a dominant negative ubiquitin mutant and in cells bearing a temperature-sensitive mutation in the ubiquitin-activating enzyme, confirming that ubiquitination is required for rapid CFTR degradation.
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PMID:Degradation of CFTR by the ubiquitin-proteasome pathway. 755 63

The T lymphocytes of the vertebrate immune system look for changes that take place within the organism by examining a display of peptides at the cell surface. These peptides are presented by the products of the major histocompatibility complex (MHC). MHC class I products present peptides derived by proteolysis of cytosolic proteins by the multicatalytic protease, the proteasome. These peptides are translocated from the cytosol into the endoplasmic reticulum by a dedicated peptide transporter, the transporter associated with antigen presentation (TAP). TAP consists of two subunits, and translocates peptides that are approximately 8-12 residues in length. The COOH terminal residue of the peptide is a major determinant in the specificity of translocation. Following translocation, peptides bind to MHC class I molecules, which depend on the peptide ligand as well as on interactions with chaperonins for proper folding. These complexes then egress from the ER and are transported to their final destination, the cell surface.
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PMID:Generation, translocation, and presentation of MHC class I-restricted peptides. 757 90

The ability of minigene-encoded viral peptide epitopes to be presented by class I molecules in the absence of MHC-encoded transporters has been evaluated in mutant T2 cells. These cells have a large deletion in the class II MHC region that includes the known transporter protein for antigenic peptides and proteasome genes and they are defective in presenting viral epitopes to CTL. T2 cells that express minigenes encoding the influenza virus matrix peptide 58-66 (GILGFVFTL) and two HTLV 1 Tax peptides 11-19 (LLFGYPVYV) and 12-19 were lysed by HLA-A2-restricted peptide-specific CTL. Minigene expression of a HLA-A2-restricted HIV reverse transcriptase peptide 476-484 (ILKEPVHGV) with three charged residues sensitized T2 cells poorly for lysis by HIV-specific CTL unless the peptide was preceded by an endoplasmic reticulum translocation signal sequence. Expression of an influenza virus nucleoprotein peptide 383-391 (SRYWAIRTR) with three charged arginine residues did sensitize HLA-B27+ T2 cells for lysis by peptide-specific CTL. These and other results with endogenously expressed peptide analogs in which hydrophobic and charged amino acids were interchanged demonstrate that antigenic peptides can be translocated from the cytoplasm into the class I Ag presentation pathway independent of MHC-encoded transporters; and that peptide hydrophobicity appears not to be a major determinant in selecting peptides for this alternate pathway.
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PMID:Presentation of endogenous peptides to MHC class I-restricted cytotoxic T lymphocytes in transport deletion mutant T2 cells. 767 94

Four genes, closely linked to major histocompatibility complex (MHC) class II genes, have been identified in humans, mice, and rats and are thought to be involved in the generation and transport of endogenous immunogenic peptides for the MHC class I antigen-processing pathway. The Tap-1 and Tap-2 genes presumably encode a heterodimeric protein complex responsible for transporting endogenous immunogenic peptides to the lumen of the endoplasmic reticulum. The Lmp-2 and Lmp-7 gene products are two subunits of the large cytosolic proteasome complex possibly involved in generation of endogenous peptides. To study the genetic polymorphism of the Lmp-2 gene, we used a published cDNA sequence as a consensus sequence and PCR-amplified, cloned, and sequenced the Lmp-2 gene from 12 inbred mouse strains. We found three amino acid variants, LMP-2d, LMP-2b, and LMP-2q, which partially correlated with restriction fragment length polymorphism variants identified with Southern blots. Allelic polymorphism of the Lmp-2 gene may be involved in peptide selection, leading to autoimmune disease susceptibility.
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PMID:Molecular basis of genetic polymorphism in major histocompatibility complex-linked proteasome gene (Lmp-2). 768 85

Recent studies have demonstrated that the proteasome, in addition to functioning in the complete degradation of cell proteins, is the source of most antigenic peptides presented to the immune system on major histocompatibility complex (MHC)-class I molecules. In this process, intracellular and viral proteins are degraded in the cytosol to 8- to 9-amino acid fragments, which are then transported into the endoplasmic reticulum, where they become associated with MHC-class I molecules and are thus delivered to the cell surface. A variety of evidence has shown that the proteasome and ATP-ubiquitin-dependent pathway are critical in this process: (1) In cells, selective inhibitors of proteasome function inhibit the bulk of protein degradation and thus prevent the generation of peptides necessary for class I presentation and the appearance of MHC on the cell surface. (2) Mutations that block ubiquitin conjugation prevent the generation of an antigenic peptide. (3) Modifications that lead to rapid degradation of a protein by the ubiquitin pathway enhance antigen presentation. (4) gamma-Interferon (gamma-IFN) induces new proteasome subunits, LMP2 and LMP7, encoded in the MHC region that are incorporated in place of constitutive proteasome subunits. Their incorporation does not affect rates of protein breakdown but causes changes in peptidase activities, i.e. they increase rates of cleavage after basic and hydrophobic residues and decrease cleavage after acidic residues. Transfections of cells with LMP2 or LMP7 cause similar changes in these peptidase activities as are caused by gamma-IFN. These modifications in peptidase activities should enhance the production of those types of peptides which are preferentially transported into endoplasmic reticulum and selectively bound to MHC-class I molecules.
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PMID:Role of proteasomes in antigen presentation. 769 33

Two pathways exist within vertebrate cells to generate peptides for recognition by T cells. The "endogenous" pathway provides peptides to MHC class I molecules for presentation to CD8+ T cells. These peptides are derived from proteins synthesized or residing in the cytoplasm or nucleus, and involves proteasomes and the ubiquitin pathway of protein degradation, as well as a specific peptide transporter (TAP) that allows these peptides access to the lumen of the endoplasmic reticulum. The exogenous pathway provides peptides to MHC class II molecules for presentation to CD4+ T cells. These peptides are derived from extracellular antigens taken up by endocytosis and degraded in the endosomal/lysosomal pathway. Peptide loading of MHC class II molecules requires the presence of a molecule (H-2M in mouse, HLA-DM in humans) that is structurally related to MHC class II molecules, but the mechanistic basis of this requirement is unknown. The class II region of the MHC contains a cluster of genes encoding proteins involved in antigen processing, including genes for two proteasome subunits (LMP2 and LMP7), the peptide transporter heterodimer (TAP1 and TAP2), and the H-2M/HLA-DM molecule (Ma and Mb, or DMA and DMB).
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PMID:Pathways for the processing and presentation of antigens to T cells. 772 12

Three observations suggest that the proteasome, transporter associated with antigen processing (TAP) and class I MHC molecules are co-adapted for the generation, transport and loading of specific peptides. Firstly, TAP preferentially transports peptides close in length to the optimum for class I loading; secondly, genetic variation in TAP specificity focusing in the carboxy-terminal of the peptide correlates with preferences among class I molecules for different peptide carboxy-termini; thirdly, TAP associates directly with empty class I molecules and is released by successful peptide loading. This conclusion puts in question the significance for class I loading of proteolytic processing and peptide generation in the endoplasmic reticulum.
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PMID:Supply and transport of peptides presented by class I MHC molecules. 777 84

Cytotoxic T lymphocytes (CTL) recognize antigenic peptides bound to major histocompatibility complex class I antigens on the cell surface of virus-infected cells. It is believed that the majority of peptides originate from cytoplasmic degradation of proteins assumed to be mediated by the "20S" proteasome. Cytosolic peptides are then translocated, presumably by transporters associated with antigen processing (TAP-1 and -2), into the lumen of the endoplasmic reticulum (ER) where binding and formation of the ternary complex between heavy chain, beta2-microglobulin (beta 2m) and peptide occurs. In this study, we have analyzed and compared the phenotype of two mutant cell lines, the thymoma cell line RMA-S and a small lung carcinoma cell line CMT.64, in order to address the mechanism that underlies the antigen processing deficiency of CMT.64 cells. Unlike RMA-S cells, vesicular stomatitis virus (VSV)-infected CMT.64 cells are not recognized by specific CTL. Interferon gamma (IFN-gamma) treatment of CMT.64 cells restores the ability of these cells to process and present VSV in the context of Kb. We show that although CMT.64 cells express a low level of beta 2m, the recognition of VSV-specific CTL is not restored by increasing the amount of beta 2m synthesized in CMT.64 cells. In addition, we find that CMT.64 cells express moderate levels of Kb heavy chain molecules, but most of it is unstable and rapidly degraded in the absence of IFN-gamma treatment. We infer that the antigen processing deficiency does not lie at the level of beta 2m or Kb production. We find also that the mRNAs for both TAP-1 and -2 are present in RMA and RMA-S cells but are absent in uninduced CMT.64 cells. Upon IFN-gamma induction, both mRNAs are highly expressed in CMT-64 cells. In addition, we find that the low molecular mass polypeptides 2 and 7, and additional components of the proteasome are induced by IFN-gamma in CMT-64 cells. Finally, introduction of the rat TAP-1 gene in CMT.64 cells restores CTL recognition of VSV-infected cells. These results indicate that a TAP-1 homodimer may translocate peptides in the ER and explain partially the CMT.64 defect and the RMA-S phenotype. These findings link a dysfunction in the transport and/or generation of antigenic peptides to the capacity of tumor cells to evade immunosurveillance and provide a unique model system to dissect this phenomenon.
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PMID:Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing. 793 Oct 74

In the class II region of the major histocompatibility complex (MHC(, four genes implicated in MHC class I-mediated antigen processing have been described. Two genes (TAP1 and TAP2) code for multimembrane-spanning ATP-binding transporter proteins and two genes (LMP2 and LMP7) code for subunits of the proteasome. While TAP1 and TAP2 have been shown to transport antigenic peptides from the cytosol into the endoplasmic reticulum, where the peptides associate with MHC class I molecules, the role of LMP2/7 in antigen presentation is less clear. Using antigen processing mutant T2 cells that lack TAP1/2 and LMP2/7 genes, it was recently shown that expression of TAP1/2 alone was sufficient for processing and presentation of the influenza matrix protein M1 as well as the minor histocompatibility antigen HA-2 by HLA-A2. To understand if presentation of a broader range of viral antigens occurs in the absence of LMP2/7, we transfected T2 cells with TAP1, TAP2 and either of the H-2Kb, Db or Kd genes and tested their ability to present vesicular stomatitis vires and influenza virus antigens to virus-specific cytotoxic T lymphocytes. We found that T2 cells, expressing TAP1/2 gene products, presented all tested viral antigens restricted through either the H-2Kb, Db or Kd class I molecules. We conclude that the proteasome subunits LMP2/7 as well as other gene products in the MHC class II region, except from TAP1/2, are not generally necessary for presentation of a broader panel of viral antigens to cytotoxic T cells. However, the present results do not exclude that LMP2/7 in a more subtle way may, or in rare cases completely, affect processing of antigen for presentation by MHC class I molecules.
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PMID:Presentation of viral antigens restricted by H-2Kb, Db or Kd in proteasome subunit LMP2- and LMP7-deficient cells. 805 44

Membrane cofactor protein (MCP, CD46), a widely distributed regulatory protein, inhibits complement activation on host cells and serves as a measles virus receptor. Most cells express four isoforms (with one of two cytoplasmic tails, CYT-1 or CYT-2). Previously, we noted that MCP precursors had variable intracellular processing. Therefore, we characterized the intracellular transport of individual MCP isoforms. Transfectants were used for pulse-chase analyses. MCP isoforms bearing CYT-1 chased into their mature, surface forms with a half-life (t1/2) of 10-13 min while those with CYT-2 required 35-40 min. The precursor of a tail-less mutant possessed a t1/2 of 160-165 min. Chimeras were constructed that added both tails in opposite orientation onto the isoform (i.e. CYT 1 + 2 or CYT 2 + 1). Chimera 1 + 2 precursor processed with a t1/2 of 35-37 min, similar to CYT-2. Chimera 2 + 1 had a t1/2 of 15-19 min, more closely resembling CYT-1. Thus, in both cases the carboxyl-terminal tail controlled the processing rate. Deletions were made in the beginning, middle, and carboxyl terminus of CYT-1. Deletion of the first or middle six amino acids had no effect on the processing rate. However, deletion of the terminal tetrapeptide (FTSL) slowed the rate to 30-32 min, suggesting that this sequence facilitates exit from the endoplasmic reticulum.
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PMID:Membrane cofactor protein (CD46) of complement. Processing differences related to alternatively spliced cytoplasmic domains. 814 66


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