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 effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.
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PMID:Identification of T-cell epitopes for cancer immunotherapy. 1761 70

The cancer-testis antigen NY-ESO-1 has been implicated as one of the most attractive candidates for a cancer vaccine. However, a protein vaccine generally meets inefficient antigen presentation to CD8(+) T cells, which could be overcome by combination with an appropriate adjuvant. Heat shock protein is a natural adjuvant and activates the antigen-presenting cells to channel exogenous antigens into the classical major histocompatibility complex class I antigen-processing pathway (cross-presentation). Therefore, we genetically fused a minigene encompassing the NY-ESO-1 cytotoxic T lymphocyte (CTL) epitope 157-165 (ESO p157-165) to the human heat shock cognate protein 70 (hsc70) and expressed the resulting fusion proteins in Escherichia coli. By using a human leukocyte antigen-A*0201-restricted NY-ESO-1-specific CTL clone, the cross-presentation of ESO p157-165 by monocyte-derived dendritic cells (mo-DC) pulsed with the fusion protein was evaluated. The fusion protein-pulsed mo-DC activates the CTL clone much more efficiently than the free NY-ESO-1 protein-pulsed mo-DC. Moreover, the magnitude of the CTL activity was comparable between ESO p157-165 and the fusion protein of hsc70 and ESO p157-165 (hsc70-ESO p157-165 fusion protein). In addition, the CTL activation induced by the fusion protein, but not by the epitope, was inhibited by paraformaldehyde fixation of the mo-DC and by treatment with lactacystin, a specific inhibitor for the proteasome. Finally, the hsc70-ESO p157-165 fusion protein-pulsed DC was able to induce an antigen-specific T-cell response. These results suggest that the hsc70-ESO p157-165 fusion protein is therefore considered to be a promising candidate as a cancer vaccine.
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PMID:Cross-presentation of NY-ESO-1 cytotoxic T lymphocyte epitope fused to human heat shock cognate protein 70 by dendritic cells. 1799 Dec 94

The molecular mechanisms of the atheroprotective effect evoked by hormone replacement therapy in postmenopausal women is not well known. Recently, we have demonstrated enhanced activity of the ubiquitin-proteasome system in human atherosclerotic plaques and evidenced that it is associated with inflammatory-induced plaque rupture. Therefore, we hypothesized that hormone replacement therapy may exert the cardioprotective effects modulating the ubiquitin-proteasome activity. To investigate this possibility, this study examined the differences in inflammatory infiltration, as well as ubiquitin-proteasome activity, between asymptomatic carotid plaques of postmenopausal women with and without concomitant hormone replacement therapy. Plaques were obtained from 20 postmenopausal women treated with hormone replacement therapy (current users) and 32 nontreated women (never-users) enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen-DR+ cells, ubiquitin-proteasome system, nuclear factor kappaB, inhibitor of nuclear factor kappaBbeta, tumor necrosis factor-alpha, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques from current users, plaques from never-users had more macrophages, T lymphocytes, and human leukocyte antigen-DR+ cells (P<0.001); more ubiquitin-proteasome activity, tumor necrosis factor-alpha, and nuclear factor kappaB (P<0.001); and more nitrotyrosine and matrix metalloproteinase-9 (P<0.001), along with a lesser collagen content and inhibitor of nuclear factor kappaBbeta levels (P<0.001). This study supports the hypothesis that hormone replacement therapy inhibits plaque ubiquitin-proteasome activity by decreasing oxidative stress generation in postmenopausal women. This effect, in turn, might contribute to plaque stabilization by inhibiting the activation of nuclear factor kappaB-dependent inflammation, responsible for plaque rupture.
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PMID:Proteasome activity as a target of hormone replacement therapy-dependent plaque stabilization in postmenopausal women. 1825 30

Soluble extracellular proteins usually do not enter the endogenous human leukocyte antigen (HLA) I-dependent presentation pathway of antigen-presenting cells, strictly impeding their applicability for the re-stimulation of protein-specific CD8(+) cytotoxic T lymphocytes (CTL). Here we present for the Epstein-Barr virus (EBV) BZLF1 a novel strategy that facilitates protein translocation into antigen-presenting cells by its solubilisation in high molar urea and subsequent pulsing of cells in presence of low molar urea. Stimulation of PBMC from HLA-matched EBV-seropositive individuals with urea-treated BZLF1 but not untreated BZLF1 induces an efficient reactivation of BZLF1-specific CTL. Urea-treated BZLF1 (uBZLF1) enters antigen-presenting cells in a temperature-dependent manner by clathrin-mediated endocytosis and is processed by the proteasome into peptides that are bound to nascent HLA I molecules. Dendritic cells and monocytes but also B cells can cross-present uBZLF1 in vitro. The strategy described here has potential for use in the development of improved technologies for the monitoring of protein-specific CTL.
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PMID:Urea-mediated cross-presentation of soluble Epstein-Barr virus BZLF1 protein. 1898 61

Heat shock protein 70 (HSPA) is a molecular chaperone which has been suggested to shuttle human leukocyte antigen (HLA) epitope precursors from the proteasome to the transporter associated with antigen processing. Despite the reported observations that peptides chaperoned by HSPA are an effective source of antigens for cross-priming, little is known about the peptides involved in the process. In this study, we investigated the possible involvement of HSPA in HLA class I or class II antigen presentation and analysed the antigenic potential of the associated peptides. HSPA was purified from CCRF-CEM and K562 cell lines, and using mass spectrometry techniques, we identified 44 different peptides which were co-purified with HSPA. The affinity of the identified peptides to two HSPA isoforms, HSPA1A and HSPA8, was confirmed using a peptide array. Four of the HSPA-associated peptides were matched with 13 previously reported HLA epitopes. Of these 13 peptides, nine were HLA class I and four were HLA class II epitopes. These results demonstrate the association of HSPA with HLA class I and class II epitopes, therefore providing further evidence for the involvement of HSPA in the antigen presentation process.
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PMID:Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA). 2035 20

The transporter associated with antigen processing (TAP) delivers the viral proteolytic products generated by the proteasome in the cytosol to the endoplasmic reticulum lumen that are subsequently recognized by cytotoxic T lymphocytes (CTLs). However, several viral epitopes have been identified in TAP-deficient models. Using mass spectrometry to analyze complex human leukocyte antigen (HLA)-bound peptide pools isolated from large numbers of TAP-deficient vaccinia virus-infected cells, we identified 11 ligands naturally presented by four different HLA-A, HLA-B, and HLA-C class I molecules. Two of these ligands were presented by two different HLA class I alleles, and, as a result, 13 different HLA-peptide complexes were formed simultaneously in the same vaccinia virus-infected cells. In addition to the high-affinity ligands, one low-affinity peptide restricted by each of the HLA-A, HLA-B, and HLA-C class I molecules was identified. Both high- and low-affinity ligands generated long-term memory CTL responses to vaccinia virus in an HLA-A2-transgenic mouse model. The processing and presentation of two vaccinia virus-encoded HLA-A2-restricted antigens took place via proteasomal and nonproteasomal pathways, which were blocked in infected cells with chemical inhibitors specific for different subsets of metalloproteinases. These data have implications for the study of the effectiveness of early empirical vaccination with cowpox virus against smallpox disease.
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PMID:Multiple viral ligands naturally presented by different class I molecules in transporter antigen processing-deficient vaccinia virus-infected cells. 2203 44

The transporter associated with antigen processing (TAP) translocates the viral proteolytic peptides generated by the proteasome and other proteases in the cytosol to the endoplasmic reticulum lumen. There, they complex with nascent human leukocyte antigen (HLA) class I molecules, which are subsequently recognized by the CD8(+) lymphocyte cellular response. However, individuals with nonfunctional TAP complexes or tumor or infected cells with blocked TAP molecules are able to present HLA class I ligands generated by TAP-independent processing pathways. Herein, using a TAP-independent polyclonal vaccinia virus-polyspecific CD8(+) T cell line, two conserved vaccinia-derived TAP-independent HLA-B*0702 epitopes were identified. The presentation of these epitopes in normal cells occurs via complex antigen-processing pathways involving the proteasome and/or different subsets of metalloproteinases (amino-, carboxy-, and endoproteases), which were blocked in infected cells with specific chemical inhibitors. These data support the hypothesis that the abundant cellular proteolytic systems contribute to the supply of peptides recognized by the antiviral cellular immune response, thereby facilitating immunosurveillance. These data may explain why TAP-deficient individuals live normal life spans without any increased susceptibility to viral infections.
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PMID:Role of metalloproteases in vaccinia virus epitope processing for transporter associated with antigen processing (TAP)-independent human leukocyte antigen (HLA)-B7 class I antigen presentation. 2286 94

Synthetic long peptides that contain immunogenic T-cell epitopes have been used to induce activation of antigen-specific CD8 T cells in vitro for immune monitoring or adoptive transfer, or in vivo after peptide vaccination. However, the efficiency and mechanisms of presentation of exogenous long peptides in human leukocyte antigen (HLA) class I remain to be elucidated. In this study, we demonstrated that the efficiency of antigen-specific CD8 T-cell activation using extended peptide variants of common viral epitopes is variable. We demonstrated that processing and HLA class I presentation of the long peptides were not dependent on the proteasome and transporter associated with antigen processing, illustrating that the classic route of HLA class I presentation was not required for activation of specific CD8 T cells by exogenous synthetic long peptides. Although long peptides were shown to bind to the relevant HLA class I molecules, peptide trimming was likely to be essential for optimal HLA class I presentation and T-cell activation. As the proteasome was not required for processing of exogenous peptides, it is very likely that peptide trimming was mediated by peptidases, which may be located extracellularly at the cell surface, in the cytosol, endoplasmic reticulum, or in endosomal and lysosomal compartments. Furthermore, the results suggested that processing of the correct minimal peptides was facilitated by binding in HLA class I molecules. This mechanism of HLA-guided processing may be important in HLA class I presentation of exogenous long peptides to induce activation of specific CD8 T cells.
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PMID:Efficiency and mechanism of antigen-specific CD8+ T-cell activation using synthetic long peptides. 2230 2

Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
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PMID:The role of antigen cross-presentation from leukemia blasts on immunity to the leukemia-associated antigen PR1. 2249 88

The broadly human leukocyte antigen (HLA) sensitized patient awaiting organ transplantation remains a persistent and significant problem for transplant medicine. Sensitization occurs as a consequence of exposure to HLA antigens through pregnancy, blood and platelet transfusions, and previous transplants. Early experience with desensitization protocols coupled with improved diagnostics for donor-specific antibodies (DSAs) and renal pathology have greatly improved transplant rates and outcomes for patients once considered un-transplantable or at high risk for poor outcomes. More recent advances have occurred through implementation of a national allocation system requiring the entering of unacceptable antigens that reduces the rate of crossmatch positivity. Current desensitization therapies include high-dose intravenous immunoglobulin (IVIG), plasma exchange (PLEX) with low-dose IVIG, and IVIG combined with rituximab. Developing therapies include proteasome inhibitors aimed at plasma cells and modifiers of complement-mediated injury. Here we discuss the important advancements in desensitization including defining the risk for antibody-mediated rejection prior to transplantation and the evolution of therapies aimed at reducing the impact of antibody injury on allografts.
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PMID:Evolving paradigms for desensitization in managing broadly HLA sensitized transplant candidates. 2254 14


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