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)

The genomic sequence of a 66,109 bp long region within the human MHC has been determined by manual and automated DNA sequencing. From cDNA mapping and sequencing data it is known that this region contains a cluster of at least four genes that are believed to be involved in antigen processing. Here, we describe the genomic organization of these genes, which comprise two proteasome-related genes (LMP2 and LMP7), thought to be involved in the proteolytic degradation of cytoplasmic antigens and two ABC transporter genes (TAP1 and TAP2), thought to be involved in pumping of the degraded peptides across the endoplasmic reticulum membrane. Analysis of the sequence homology and the intron/exon structures of the corresponding genes suggests that one gene pair arose by duplication from the other. Comparison of the available sequence data from other organisms shows striking conservation (70 to 84%) of this gene cluster in human, mouse and rat. The presence of several potential interferon stimulated response elements (ISREs) is in agreement with the experimentally observed up-regulation of these genes with gamma-interferon.
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PMID:DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing. 145 54

The recent discovery of two proteasome homologous genes, LMP2 and LMP7, in the class II region of the human MHC, has implicated this multi-subunit protease in an early step of the immune response; the degradation of intracellular and viral proteins. Short peptides produced by the proteasome are transported into the ER by the product of another set of MHC class II genes, TAP1 and TAP2, where they bind and stabilise HLA class I molecules. Antigenic peptides displayed at the cell surface by HLA class I molecules mark cells for destruction by cytotoxic T lymphocytes. The role of the proteasome in antigen processing was questioned when mutant cells, which lack the LMP genes, were able to process and present antigens normally. The discovery that two proteasome beta-subunits, delta and MB1, highly homologous to LMP2 and LMP7 and expressed in reciprocal manner, is now consistent with a role for the proteasome in antigen processing. The incorporation of different beta-subunits into the proteasome may be a mechanism to modulate catalytic activity of the proteasome complex, allowing production of peptides that are more suitable to enter into the ER by the TAP transporters and to bind HLA class I molecules. But, in the absence of the LMPs, the other subunits permit processing of most antigens reasonably efficiently.
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PMID:Proteasome and class I antigen processing and presentation. 756 65

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

Peptides from endogenous proteins are presented by major histocompatibility complex class I molecules, but antigens (Ags) in the extracellular fluids are generally not. However, pathogens or particulate Ags that are internalized into phagosomes of macrophages (M phi s) stimulate CD8 T cells. The presentation of these Ags is resistant to chloroquine but is blocked by inhibitors of the proteasome, a mutation in the TAP1-TAP2 transporter, and brefeldin A. Moreover, phagocytosis of a ribosomal-inactivating protein inhibited M phi protein synthesis. These results demonstrate that M phi s transfer Ags from phagosomes into the cytosol and that endogenous and exogenous Ags use a final common pathway for class I presentation.
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PMID:A phagosome-to-cytosol pathway for exogenous antigens presented on MHC class I molecules. 780 29

The B cell line 721.174 has lost the ability to present intracellular antigens to major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL). This phenotype results from a homozygous deletion in the MHC that includes the peptide transporter genes TAP1 and TAP2, and the proteasome subunits LMP2 and LMP7. Recent work has shown that such cells transfected with TAP genes load their class I molecules with endogenous peptides, and present several viral epitopes to class I-restricted CTL. These data implied that the LMP2 and LMP7 genes were not required for the presentation of most epitopes through class I molecules. By contrast, while confirming the previous reports, we have identified several epitopes that appear to require genes in the MHC in addition to the TAP for their presentation. Further analysis localizes the defect to proteolysis in the cytosol. In one case, presentation could be partially restored by re-expression of full-length LMP7. Control experiments with LMP7, from which the putative pro-region had been removed, failed to restore presentation, and this lack of effect correlated with failure of the shortened LMP7 to incorporate into the proteasome. These results suggest a role for LMP7 in the generation of a viral epitope, but leave open the possibility that additional genes within the .174 deletion are required for full restoration of antigen presentation.
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PMID:Genes encoded in the major histocompatibility complex affecting the generation of peptides for TAP transport. 787 20

We have earlier described an alternative MHC class I processing pathway for Sendai virus (SV) in H-2Kb-transfected T2 cells (T2Kb). These cells have deleted genes for transporters associated with Ag processing (TAP1/2) and proteasome subunits LMP2/7 but can still process SV for the presentation of an immunodominant nucleoprotein CTL epitope (nucleoprotein peptide 324-332, FAPGNYPAL, SV9), even in the presence of the fungal metabolite brefeldin A (BFA). Presently we have compared live and heat-inactivated SV to investigate whether infectious virus, including early events such as binding and fusion at the host cell membrane, is important for nonclassical MHC class I processing and immunogenicity. We have found that heated virus (56 degrees C, boiled or autoclaved) with no fusion and hemagglutinin-neuraminidase activities, behaves similar to live SV in T2kb cells by entering a TAP-independent and BFA-resistant pathway. In EL-4 cells, which do not express this nonclassical TAP-independent and BFA-resistant pathway, heat-treated SV is processed in a BFA-sensitive way. In T1Kb- and TAP1/2-transfected T2Kb cells, as in T2Kb cells, processing of heat-inactivated SV was completely BFA resistant. Heat-inactivated SV was also found to prime CTLs in vivo. We conclude that heat-inactivated SV can enter both BFA-sensitive and -resistant MHC class I processing pathways and that SV in this respect may be particularly efficient. What property in the SV that is important for this characteristic is presently not clear but might be useful for the deliberate generation of CTL responses in vivo.
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PMID:Heat-inactivated Sendai virus can enter multiple MHC class I processing pathways and generate cytotoxic T lymphocyte responses in vivo. 789 4

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

The processing pathway for the MHC class II-restricted presentation of endogenous cytosolic Ag is distinct from the class I pathway since a cytosolic form of the influenza virus A hemagglutinin, expressed by a recombinant vaccinia virus, was presented by HLA-DR in a B cell mutant lacking the TAP1 subunit of the transporter for Ag presentation (TAP). In this report, two additional B cell mutants have been used to define the requirements of this TAP1-independent processing pathway. The first mutant, .61, lacks expression of both TAP1 and TAP2 genes, and of both LMP2 and LMP7 genes encoding proteasome subunits. As expected, class I-restricted presentation of the influenza virus matrix protein was totally deficient in mutant .61. In contrast, class II-restricted presentation of both the natural cytosolic matrix and the engineered cytosolic hemagglutinin proteins was functional in mutant .61. Thus, presentation of cytosolic Ag by class II molecules is independent of both TAP subunits and of the two MHC-encoded proteasome subunits. However, this endogenous processing pathway is dependent on at least one other function encoded in the class II region of the MHC as demonstrated with the second mutant, .174, in which a large deletion eliminates all expressed class II genes. Mutant .174 transfected with HLA-DR1 genes was previously shown to be defective in the presentation of exogenous Ag but normal in the presentation of short exogenous peptides. We show here that .174(DR1) is also defective in the presentation of cytosolic matrix and hemagglutinin proteins. This similar requirement for the class II-restricted presentation of either cytosolic Ag or internalized exogenous Ag suggests that both forms of Ag are ultimately targeted to the same cellular compartment for association with class II molecules.
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PMID:Presentation of cytosolic antigen by HLA-DR requires a function encoded in the class II region of the MHC. 825 89

Latex-OVA and bacteria expressing an OVA fusion protein were processed by macrophages via an alternate class I MHC (MHC-I) processing pathway to present OVA(257-264):Kb. This pathway was resistant to dipeptide aldehyde proteasome inhibitors and brefeldin A, unlike the cytosolic MHC-I pathway. TAP1-/- macrophages exhibited decreases in cell surface peptide-receptive MHC-I and binding of extracellular peptide during transient incubations. This may explain an apparent influence of TAP on alternate MHC-I processing. Alternate MHC-I processing by TAP1-/- cells was enhanced by preincubation at 26 degrees C or with beta 2-microglobulin to increase peptide-receptive MHC-I. Thus, peptides may bind to MHC-I within post-Golgi vacuolar organelles accessible to exogenous beta 2-microglobulin or on the cell surface (following peptide regurgitation).
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PMID:Roles of proteasomes, transporter for antigen presentation (TAP), and beta 2-microglobulin in the processing of bacterial or particulate antigens via an alternate class I MHC processing pathway. 866 86

HLA class I antigens of the human major histocompatibility complex play an important role in immune response. These molecules present foreign antigenic peptides to cytotoxic T lymphocytes and thereby play a role in the immune surveillance of cells infected with virus or other intracellular pathogens or altered by malignant transformation. A marked deficiency or lack of expression of these antigens has been reported in a variety of human neoplasms. In the present study, we examined the expression of class I alpha chain, beta 2-microglobulin, TAP (TAP1 and TAP2) and LMP (LMP2 and LMP7) genes in a number of human tumor cell lines including small-cell lung carcinoma, hepatocellular carcinoma, colon adenocarcinoma and basophilic leukaemia. These cell lines were deficient in expression of both class I alpha chain and beta 2-microglobulin gene products. In addition, these cell lines lacked the products of MHC-encoded proteasome subunit LMP2 as well as the putative peptide transporter TAP1 genes. In contrast, TAP2 and LMP7 genes were expressed in these cell lines. Treatment of cells with gamma-IFN markedly enhanced the expression of class I alpha chain, beta 2-microglobulin, TAP1 and LMP2 genes with a concomitant increase in cell-surface expression of class I molecules. The upregulation of TAP1 and LMP2 expression is associated with increased class I expression, suggesting that endogenous antigens, e.g. tumor antigens, could be presented by class I molecules following treatment of tumor cells with gamma-IFN.
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PMID:Markedly decreased expression of TAP1 and LMP2 genes in HLA class I-deficient human tumor cell lines. 880 12


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