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)

Sequence-independent interactions involving the free peptidic NH(2) terminus are thought to be an essential feature of peptide binding to classical major histocompatibility complex (MHC) class I proteins. Challenging this paradigm, a natural Nalpha-acetylated ligand of human histocompatibility leukocyte antigen (HLA)-B39 was identified in this study. It matched the NH(2)-terminal sequence of two human helicases, was resistant to aminopeptidase M, and was produced with high yield from a synthetic 30 mer with the sequence of the putative parental protein by the 20S proteasome. This is the first reported natural ligand of classical MHC class I antigens that has a blocked NH(2) terminus.
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PMID:An N-acetylated natural ligand of human histocompatibility leukocyte antigen (HLA)-B39. Classical major histocompatibility complex class I proteins bind peptides with a blocked NH(2) terminus in vivo. 1085 33

The phagosome fraction derived from a murine macrophage cell line (J774.1), which had internalized ovalbumin (OVA)-coated latex beads, was isolated. The peptides recovered from the phagosome fraction were separated on reverse phase HPLC and each fraction was analyzed for the content of either major histocompatibility complex (MHC) class I- or class II-restricted OVA-derived peptide. Both peptides were detected in the phagosome fraction after less than 15 min of internalization. It was also indicated that phagosomes degrade OVA protein into both MHC class I- and class II-restricted antigenic peptides by employing the same types of cathepsins. Furthermore, the results suggest that the MHC class I-restricted peptide rapidly exits from the phagosome to the cytosol. These findings illustrate a potential role for phagosomes not only in MHC class II-restricted but also in MHC class I-restricted exogenous antigen presentation pathways. Our results also point to the vital role of phagosomes in non-cytosolic antigen presentation pathway, in which further degradation of antigens by the proteasome is dispensable.
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PMID:Generation of both MHC class I- and class II-restricted antigenic peptides from exogenously added ovalbumin in murine phagosomes. 1092 92

The proteasome is the principal provider of major histocompatibility complex (MHC) class I-presented peptides. Interferon (IFN)-gamma induces expression of three catalytically active proteasome subunits (LMP2, LMP7, and MECL-1) and the proteasome-associated activator PA28. These molecules are thought to optimize the generation of MHC class I-presented peptides. However, known information on their contribution in vivo is very limited. Here, we examined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycline-controlled, IFN-gamma-independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The presence of either immunosubunits or PA28 did not alter the presentation of a subdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the presentation of the immunodominant MuLV-derived epitope was markedly enhanced upon induction of each of these two sets of genes. Thus, the IFN-gamma-inducible proteasome subunits and PA28 can independently enhance antigen presentation of some CTL epitopes. Our data show that tetracycline-regulated expression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN-gamma-inducible proteins on MHC class I processing may have a decisive influence on the quality of the CTL immune response.
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PMID:Differential influence on cytotoxic T lymphocyte epitope presentation by controlled expression of either proteasome immunosubunits or PA28. 1095 18

Liposome-encapsulated conalbumin (L(conalbumin)) is an antigen that is efficiently phagocytosed by bone marrow-derived macrophages and presented to effector cells as part of the major histocompatibility complex (MHC) class I complex. In this report, we show that the conalbumin component of L(conalbumin) is degraded to small peptide fragments and translocated to the area of the Golgi. Golgi localization is confirmed by co-localization of L(Texas red-conalbumin) (L(TR-conalbumin))with both NBD-ceramide, a lipid Golgi marker, and green fluorescent protein (GFP)-galactosyl transferase, a Golgi resident enzyme. Incubation of the cells with brefeldin A disrupts the Golgi and disperses the TR-conalbumin. Furthermore, when macrophages were incubated with another liposome-encapsulated antigen, L(ovalbumin), ovalbumin peptides were observed in the Golgi area and MHC class I-peptide complexes could be detected on the cell surface by both immunofluorescence microscopy and flow cytometry. The Golgi localization observed in vitro in cultured macrophages is mirrored by the in vivo uptake and Golgi localization of fluorescent L(conalbumin) in macrophages isolated from the spleen of a mouse injected with L(TR-conalbumin). The accumulation of peptide fragments in the Golgi is inhibited by the addition of the proteasome inhibitors, lactacystin and MG-132, demonstrating the role of the proteasome in this activity. In addition, when macrophages or a macrophage-derived cell line, are incubated with liposome-enccapsulated antigens and used as target cells in a cytotoxic T-cell (CTL) assay, the CTLs recognize the processed peptide-MHC complexes and kill the cells. In contrast, specific lysis of target cells by CTLs is inhibited when the target cells are first incubated with lactacystin. These results suggest that uptake and processing of L(antigen) follows the classical MHC class I pathway.
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PMID:Proteasome inhibitors block the entry of liposome-encapsulated antigens into the classical MHC class I pathway. 1099 90

Type 1 diabetes is believed to be caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of Type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has now been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays an important role in immune and inflammatory responses, in addition to increasing the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The proteasome dysfunction is both tissue- and developmental stage-specific and likely contributes to disease pathogenesis and tissue targeting.
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PMID:The role of the proteasome in autoimmunity. 1102 57

We have examined the possibility that the E7 proteins of the high-risk human papillomavirus (HPV) type 16 and 18 and the oncogenic adenovirus (Ad) type 12 E1A protein share the ability to down-regulate the expression of components of the antigen processing and presentation pathway, as a common strategy in the evasion of immune surveillance during the induction of cell transformation. Expression of the HPV 18 E7 oncoprotein, like Ad 12 E1A, resulted in repression of the major histocompatibility complex (MHC) class I heavy chain promoter, as well as repression of a bidirectional promoter that regulates expression of the genes encoding the transporter associated with antigen processing subunit 1 (TAP1) and a proteasome subunit, low molecular weight protein 2 (LMP2). HPV 16 E7 also caused a reduction in class I heavy chain promoter activity, however it did not have any significant effect on the activity of the bidirectional promoter. Interestingly, expression of the low-risk HPV 6b E7 protein resulted in an increase in MHC class I heavy chain promoter activity, while repressing the TAP1/LMP2 promoter. Interference with the class I pathway could also explain the ability of low-risk HPVs in inducing benign lesions.
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PMID:Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins. 1103 10

The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides. The proteases responsible for the final NH2-terminal trimming of the precursor peptides had, until now, not been determined. By using specific selective criteria we purified two cytosolic proteolytic activities, puromycin-sensitive aminopeptidase and bleomycin hydrolase. These proteases could remove NH2-terminal amino acids from the vesicular stomatitis virus nucleoprotein cytotoxic T cell epitope 52-59 (RGYVYQGL) resulting, in combination with proteasomes, in the generation of the correct epitope. Our data provide evidence for the existence of redundant systems acting downstream of the proteasome in the antigen-processing pathway for MHC class I molecules.
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PMID:Two new proteases in the MHC class I processing pathway. 1106 1

In murine tumor cell lines, downregulation of MHC class I surface expression has been frequently detected, but the underlying molecular mechanisms of such deficiencies have not been defined. In this study, murine tumor cell lines of different histology derived from spontaneous or from chemical-induced tumors were analyzed for the expression of multiple components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM), including the peptide transporter TAP, the interferon (IFN)-gamma inducible proteasome subunits and several chaperones. The tumor cell lines analyzed demonstrated a heterogeneous expression pattern of various APM components. In comparison to control cells an impaired coordinated expression of at least three APM components was detected. In particular, extensive APM deficiencies were found in cell lines derived from chemical-induced tumors. A strong coordinated downregulation of expression and/or function of TAP, the low molecular weight proteins (LMP) subunits, the proteasome activator PA28 and/or tapasin was found in 5 of 10 tumor cells, which was associated with impaired MHC class I surface expression. In contrast, the expression of beta2-microglobulin (beta2-m), PA28beta, the constitutive proteasome subunits X, Y, Z and of the chaperones calnexin, calreticulin, ER60 and phospho disulfide isomerase (PDI) was unaltered or only weakly decreased. The deficient expression of APM components could be corrected by IFN-gamma treatment, which also reconstituted MHC class I surface expression. However, impaired expression of APM molecules appears not to be the only cause of abnormal MHC class I expression, since it could neither be corrected by the addition of exogeneous MHC class I binding peptides nor by incubation at low temperature. These results suggest that one major mechanism of murine tumor cells, in particular chemical-induced tumors, to evade the immune system is the combined dysregulation of various APM components and other factors, which still have to be identified.
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PMID:Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. 1109 32

The bulk of antigens that are presented by major histocompatibility complex (MHC) class I molecules are processed in the cytosol. Therefore, the cellular protein degradation machinery is thought to play a major role in antigen processing. For example, there is clear evidence that the ubiquitin-proteasome pathway, the major proteolytic pathway in the cytosol, plays a role in the processing of class I-associated antigens. In addition, peptide chaperones must exist to properly target peptides to the transporter associated with antigen processing. Here, the author reviews some of the more important advances over the past year that further define the pathways of antigen breakdown in the cytosol. This includes a look at the distinctive roles of proteasomes versus immunoproteasomes, the isolation of peptide processing intermediates in the cytosol, and the role of defective ribosomal products. These findings highlight the importance of understanding basic cellular protein degradation pathways in antigen processing.
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PMID:Peptide generation in the major histocompatibility complex class I antigen processing and presentation pathway. 1113 20

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
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PMID:A role for NF-kappaB and the proteasome in autoimmunity. 1114 Apr 62


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