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)

We have developed an approach to human developmental biology which exploits somatic cell genetics. With this system we have examined the production of the HLA-A,B,C antigens, A human-mouse somatic cell hybrid was constructed which contained a human X-7 chromosome translocation carrying the HLA region; this hybrid was used as a donor of the X-6 translocation in the technique of microcell transfer. The X-6 chromosome recipient was the mouse embryonal carcinoma cell line PCC4. The microcell hybrid MCP-6 retained the embryonal carcinoma phenotype as judged by shape and absence of H-2 expression. Nonetheless, the expression of the HLA-A,B,C genes was not extinguished. HLA-A,B,C antigen production of the cell surface, however, was not detected because this hybrid apparently could not make beta 2-microglobulin.
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PMID:Introduction of a human X-6 translocation chromosome into a mouse teratocarcinoma: investigation of control of HLA-A, B, C expression. 695 Nov 67

T-cells recognize antigenic peptides associated with HLA molecules belonging to Class I (HLA-A, -B, or -C) or Class II (HLA-DP, -DQ, -DR). Roughly, Class I HLA molecules represent antigens to cytotoxic CD8+ T-cells and Class II HLA molecules to helper CD4+ T-cells. Class II HLA molecules primarily present "exogenic" peptides that penetrate within cells by endocytosis, whereas Class I HLA molecules present "endogenic" peptides produced within cells. In both cases, the mechanisms of antigen presentation are closely liked to the biosynthesis of HLA molecules and to the expression of other molecules including proteasome (LMP) and the peptide transporters (TAP) needed to transport peptides through the endoplasmic reticulum in the case of Class I molecules, and invariant chain (Ii) and HLA-DM antigens in the case of Class II molecules. In addition, "exogenous" presentation by Class I molecules has recently been described, and may be relatively specific of phagocytic cells such as macrophages.
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PMID:[Antigen presentation and macrophages]. 924 34

An association between oncogenic transformation and repression of different components of the MHC class I antigen processing machinery (APM) have been described in murine model systems. In order to discover whether a similar correlation exists, human tumor cell lines of distinct histology with altered ras protein were analyzed for the expression of APM components utilizing RT-PCR and Western blot analyses. A heterogeneous expression pattern of MHC class I antigens, TAP peptide transporter, proteasome subunits, proteasome activator PA28 and the chaperones calnexin, calreticulin as well as tapasin was displayed by these tumor cell lines. Single or combined deficiencies in the expression and/or function of TAP, LMP2, LMP10 and tapasin were demonstrated in 11 of 12 cell lines studied, whereas the expression of calnexin, calreticulin, beta2-microglobulin, LMP7 and PA28alpha was unaltered or only weakly decreased. The impaired expression of TAP, LMP subunits and tapasin was not associated with altered ras, but resulted in reduced MHC class I surface expression. In particular, a significant allele- and locus-specific downregulation of the HLA-A and HLA-B haplotypes was found. IFN-gamma treatment corrected the TAP, LMP and tapasin deficiencies and enhanced the constitutive PA28alpha, LMP7, calnexin and calreticulin expression which was accompanied with increased levels of MHC class I antigens. Thus, dysregulation rather than structural alterations of different APM components might be one mechanism of colon carcinoma, small cell lung carcinoma and pancreatic carcinoma cell lines to evade immune recognition.
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PMID:Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin. 1093 98

We report the efficient identification of four human histocompatibility leukocyte antigen (HLA)-A(*)0201-presented cytotoxic T lymphocyte (CTL) epitopes in the tumor-associated antigen PRAME using an improved "reverse immunology" strategy. Next to motif-based HLA-A(*)0201 binding prediction and actual binding and stability assays, analysis of in vitro proteasome-mediated digestions of polypeptides encompassing candidate epitopes was incorporated in the epitope prediction procedure. Proteasome cleavage pattern analysis, in particular determination of correct COOH-terminal cleavage of the putative epitope, allows a far more accurate and selective prediction of CTL epitopes. Only 4 of 19 high affinity HLA-A(*)0201 binding peptides (21%) were found to be efficiently generated by the proteasome in vitro. This approach avoids laborious CTL response inductions against high affinity binding peptides that are not processed and limits the number of peptides to be assayed for binding. CTL clones induced against the four identified epitopes (VLDGLDVLL, PRA(100-108); SLYSFPEPEA, PRA(142-151); ALYVDSLFFL, PRA(300-309); and SLLQHLIGL, PRA(425-433)) lysed melanoma, renal cell carcinoma, lung carcinoma, and mammary carcinoma cell lines expressing PRAME and HLA-A(*)0201. This indicates that these epitopes are expressed on cancer cells of diverse histologic origin, making them attractive targets for immunotherapy of cancer.
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PMID:Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis. 1113 22

The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reticulum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome. We demonstrate that the endoplasmic reticulum-lumenal domain of US2 allows tight interaction with class I molecules encoded by the HLA-A locus. Recombinant soluble US2 binds properly folded, peptide-containing recombinant HLA-A2 molecules in a peptide sequence-independent manner, consistent with US2's ability to broadly downregulate class I molecules. The physicochemical properties of the US2/MHC class I complex suggest a 1:1 stoichiometry. These results demonstrate that US2 does not require additional cellular proteins to specifically interact with soluble class I molecules. Binding of US2 does not significantly alter the conformation of class I molecules, as a soluble T-cell receptor can simultaneously recognize class I molecules associated with US2. The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US2 binds several HLA-A locus products while being unable to bind recombinant HLA-B7, HLA-B27, HLA-Cw4, or HLA-E. We did not observe interaction between soluble US2 and either recombinant HLA-DR1 or recombinant HLA-DM. The substrate specificity of US2 may help explain the presence in human cytomegalovirus of multiple strategies for downregulation of MHC class I molecules.
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PMID:Human cytomegalovirus US2 endoplasmic reticulum-lumenal domain dictates association with major histocompatibility complex class I in a locus-specific manner. 1133 1

The HLA system, which represents the major histocompatibility complex (MHC) of man, encompasses approximately one thousandth of the human genome and is localised on the short arm of chromosome 6 (band 6p 21.3). The HLA gene complex shows an extreme polymorphism which can be demonstrated by molecular genetic methods. The genes so far recognised in the HLA can be subdivided into three major classes: 1) the HLA class I (HLA-ABC) and class II genes (HLA-D); 2) immune function related genes (C2, C4A, C4B, TNFA and TNFB, transporter and proteasome genes); 3) other genes apparently not related to immune functions (CYP 21, valyl-tRNA synthetase). The loci HLA-A, -B, and -C represent the classical HLA class I loci with gene products expressed on nearly all nucleated cells; HLA-E, -F and -G the non-classical HLA class I loci, code for products with a limited tissue distribution and a restricted polymorphism. Classical class I and II MHC antigens are integral membrane proteins composed of two pairs of structurally similar extracellular domains. The X-ray studies indicated the presence of peptides bound to HLA molecules within the groove. The groove has on its floor several amino acids where peptides, derived from the antigen being presented, are bound. Although the principle of allele specific motives ruling the peptide binding seems to be become more established, the further biological impact of the allelic variation remains subject for future studies.
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PMID:[Histocompatibility HLA system of man. Consideration in the light of current concepts. I. Organization and polymorphism]. 1160 84

"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific antigens that have been used in therapeutic vaccination trials of cancer patients. It was previously demonstrated that MAGE-1 peptide KVLEYVIKV was presented by HLA-A 0201 molecules on the surface of a human breast carcinoma cell line, but no human specific CTL had been isolated so far. Here, we have used HLA-A2/MAGE-1 fluorescent multimers to isolate from blood cells three human CTL clones that recognized the MAGE-1 peptide. These clones killed efficiently HLA-A2 tumor cells expressing MAGE-1, whether or not they were treated with IFN-gamma, suggesting that the MAGE-1 antigen is processed efficiently by both the standard proteasome and the immunoproteasome. These results indicate that the MAGE-1.A2 peptide can be used for antitumoral vaccination.
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PMID:A MAGE-1 antigenic peptide recognized by human cytolytic T lymphocytes on HLA-A2 tumor cells. 1602 63

Cleavage by the proteasome is responsible for generating the C terminus of T-cell epitopes. Modeling the process of proteasome cleavage as part of a multi-step algorithm for T-cell epitope prediction will reduce the number of non-binders and increase the overall accuracy of the predictive algorithm. Quantitative matrix-based models for prediction of the proteasome cleavage sites in a protein were developed using a training set of 489 naturally processed T-cell epitopes (nonamer peptides) associated with HLA-A and HLA-B molecules. The models were validated using an external test set of 227 T-cell epitopes. The performance of the models was good, identifying 76% of the C-termini correctly. The best model of proteasome cleavage was incorporated as the first step in a three-step algorithm for T-cell epitope prediction, where subsequent steps predicted TAP affinity and MHC binding using previously derived models.
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PMID:Class I T-cell epitope prediction: improvements using a combination of proteasome cleavage, TAP affinity, and MHC binding. 1652 30

The melanocyte differentiation Ag RAB38/NY-MEL-1 was identified by serological expression cloning (SEREX) and is expressed in the vast majority of melanoma lesions. The immunogenicity of RAB38/NY-MEL-1 has been corroborated previously by the frequent occurrence of specific Ab responses in melanoma patients. To elucidate potential CD8 T cell responses, we applied in vitro sensitization with overlapping peptides spanning the RAB38/NY-MEL-1 protein sequence and the reverse immunology approach. The identified peptide RAB38/NY-MEL-1(50-58) exhibited a marked response in ELISPOT assays after in vitro sensitization of CD8 T cells from HLA-A *0201(+) melanoma patients. In vitro digestion assays using purified proteasomes provided evidence of natural processing of RAB38/NY-MEL-1(50-58) peptide. Accordingly, monoclonal RAB38/NY-MEL-1(50-58)-specific T cell populations were capable of specifically recognizing HLA-A2(+) melanoma cell lines expressing RAB38/NY-MEL-1. Applying fluorescent HLA-A2/RAB38/NY-MEL-1(50-58) multimeric constructs, we were able to document a spontaneously developed memory/effector CD8 T cell response against this peptide in a melanoma patient. To elucidate the Ag-processing pathway, we demonstrate that RAB38/NY-MEL-1(50-58) is produced efficiently by the standard proteasome and the immunoproteasome. In addition to the identification of a RAB38/NY-MEL-1-derived immunogenic CD8 T cell epitope, this study is instrumental for both the onset and monitoring of future RAB38/NY-MEL-1-based vaccination trials.
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PMID:Spontaneous CD8 T cell responses against the melanocyte differentiation antigen RAB38/NY-MEL-1 in melanoma patients. 1711 98

Proteasomes are known to produce major histocompatibility complex (MHC) class I ligands from endogenous antigens. The interferon-gamma-inducible proteasome activator PA28 plays an important role in the generation of MHC ligands by proteasomes. Generation of the HLA-A(*)0201 restricted melanoma antigen TRP2(360-368) by the proteasome has been shown to be dependent on the function of PA28 in vitro and in vivo (Sun, Y., Sijts, A. J., Song, M., Janek, K., Nussbaum, A. K., Kral, S., Schirle, M., Stevanovic, S., Paschen, A., Schild, H., Kloetzel, P. M., and Schadendorf, D. (2002) Cancer Res. 62, 2875-2882). Here we analyzed the role of the epitope sequence environment in determining this PA28 dependence. Experiments using the melanoma TRP2(288-296) epitope and the murine cytomegalovirus-derived pp89 epitope precursor peptide for epitope replacement revealed that the TRP2(360-368) flanking sequences can transfer PA28 dependence onto otherwise PA28 independent epitopes. Moreover, the N-terminal flanking sequence is sufficient to establish PA28 dependence of an epitope by allowing PA28-induced coordinated dual cleavages. These results show that N-terminal flanking sequences strongly influence epitope generation efficiency and that PA28 function is particularly relevant for the generation of normally poorly excised peptide products.
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PMID:The N-terminal flanking region of the TRP2360-368 melanoma antigen determines proteasome activator PA28 requirement for epitope liberation. 1730 6


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