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)

PA28 is an interferon (gamma) (IFN(gamma)) inducible proteasome activator required for presentation of certain major histocompatibility (MHC) class I antigens. Under basal conditions in HeLa and Hep2 cells, a portion of nuclear PA28 is concentrated at promyelocytic leukemia oncoprotein (PML)-containing bodies also commonly known as PODs or ND10. IFN(gamma) treatment greatly increased the number and size of the PA28- and PML-containing bodies, and the effect was further enhanced in serum-deprived cells. PML bodies are disrupted in response to certain viral infections and in diseases such as acute promyelocytic leukemia (APL). Like PML, PA28 was delocalized from PML bodies by expression of the cytomegalovirus protein, IE1, and in NB4 cells, an APL model line. Moreover, retinoic acid treatment, which causes remission of APL in patients and reformation of PML-containing bodies in NB4 cells, relocalized PA28 to this site. In contrast, the proteasome, the functional target of PA28, was not detected at PML bodies under basal conditions in HeLa and Hep2 cells, but IFN(gamma) promoted accumulation of 'immunoproteasomes' at this site. These results establish PA28 as a novel component of nuclear PML bodies, and suggest that PA28 may assemble or activate immunoproteasomes at this site as part of its role in proteasome-dependent MHC class I antigen presentation.
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PMID:Interferon gamma regulates accumulation of the proteasome activator PA28 and immunoproteasomes at nuclear PML bodies. 1111 87

In mammalian cells proteasomes can be activated by two different types of regulatory complexes which bind to the ends of the proteasome cylinder. Addition of two 19 S (PA700; ATPase) complexes forms the 26 S proteasome, which is responsible for ATP-dependent non-lysosomal degradation of intracellular proteins, whereas 11 S complexes (PA28; REG) have been implicated in antigen processing. The PA28 complex is upregulated in response to gamma-interferon (gamma-IFN) as are three non-essential subunits of the 20 S proteasome. In the present study we have investigated the effects of gamma-IFN on the level of different proteasome complexes and on the phosphorylation of proteasome subunits. After treatment of cells with gamma-IFN, the level of 26 S proteasomes decreased and there was a concomitant increase in PA28-proteasome complexes. However, no free 19 S regulatory complexes were detected. The majority of the gamma-IFN-inducible proteasome subunits LMP2 and LMP7 were present in PA28-proteasome complexes, but these subunits were also found in 26 S proteasomes. The level of phosphorylation of both 20 S and 26 S proteasome subunits was found to decrease after gamma-IFN treatment of cells. The C8 alpha subunit showed more than a 50% decrease in phosphorylation, and the phosphorylation of C9 was only barely detectable after gamma-IFN treatment. These results suggest that association of regulatory components to 20 S proteasomes is regulated, and that phosphorylation of proteasome alpha subunits may be one mode of regulation.
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PMID:gamma-Interferon decreases the level of 26 S proteasomes and changes the pattern of phosphorylation. 1113 93

The murine B16 melanoma system represents an important in vivo model for the evaluation of T cell-based immunization and vaccination strategies, although deficient MHC class I surface expression has been identified in these cells. We postulate here that the MHC class I-deficient phenotype of B16 melanoma cells is attributable to down-regulation or the loss of the expression and function of multiple components of the MHC class I antigen-processing pathway, including the peptide transporter associated with antigen processing, the proteasome subunits LMP2, LMP7, and LMP10, PA28alpha and -beta, and the chaperone tapasin. In contrast, calnexin, calreticulin, ER60, and protein disulfide isomerase expression are unaltered or only marginally suppressed in these cells. The level of down-regulation of the components of the antigen-processing pathway is either transcriptionally or posttranscriptionally controlled and could be corrected in all cases by IFN-y treatment, which also reconstituted MHC class I surface expression. Thus, B16 melanoma cells can be used as a model for the characterization of the mechanisms underlying the coordinated dysregulation of the antigen-processing components, which should provide new insights into the development of tumors and the factors controlling this process.
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PMID:Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. 1122 38

In accordance with the key role of MHC class I molecules in the adaptive immune response against viruses, they are expressed by most cells, and their expression can be enhanced by cytokines. The assembly and cell surface expression of class I complexes depend on a continuous peptide supply. The peptides are generated mainly by the proteasome and are transported to the endoplasmic reticulum by a peptide transport pump consisting of two subunits, TAP1 and TAP2. The proteasome low molecular weight polypeptide (2 and 7), as well as TAP (1 and 2) genes, are coordinately regulated and are induced by IFNs. Despite this coordinate regulation, examination of tumors shows that these genes can be discordantly down-regulated. In pursuing a molecular explanation for these observations, we have characterized the mouse TAP2 promoter region and 5'-flanking sequence. We show that the 5' untranslated regions of TAP2 genes have a characteristic genomic organization that is conserved in both the mouse and the human. The mouse TAP2 promoter belongs to a class of promoters that lack TATA boxes but contain a MED1 (multiple start site element downstream) sequence. Accordingly, transcription is initiated from multiple sites within a 100-nucleotide window. An IFN regulatory factor 1 (IRF1)/IRF2 binding site is located in this region and is involved in both basal and IRF1-induced TAP2 promoter activity. The implication of the extensive differences found among the promoters of class I heavy chain, low molecular weight polypeptide, and TAP genes, all encoding proteins involved in Ag presentation, is discussed.
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PMID:Organization and functional analysis of the mouse transporter associated with antigen processing 2 promoter. 1123 39

Previous work has demonstrated that the V protein of simian virus 5 (SV5) targets STAT1 for proteasome-mediated degradation (thereby blocking interferon [IFN] signaling) in human but not in murine cells. In murine BF cells, SV5 establishes a low-grade persistent infection in which the virus fluxes between active and repressed states in response to local production of IFN. Upon passage of persistently infected BF cells, virus mutants were selected that were better able to replicate in murine cells than the parental W3 strain of SV5 (wild type [wt]). Viruses with mutations in the Pk region of the N-terminal domain of the V protein came to predominate the population of viruses carried in the persistently infected cell cultures. One of these mutant viruses, termed SV5 mci-2, was isolated. Sequence analysis of the V/P gene of SV5 mci-2 revealed two nucleotide differences compared to wt SV5, only one of which resulted in an amino acid substitution (asparagine [N], residue 100, to aspartic acid [D]) in V. Unlike the protein of wt SV5, the V protein of SV5 mci-2 blocked IFN signaling in murine cells. Since the SV5 mci-2 virus had additional mutations in genes other than the V/P gene, a recombinant virus (termed rSV5-V/P N(100)D) was constructed that contained this substitution alone within the wt SV5 backbone to evaluate what effect the asparagine-to-aspartic-acid substitution in V had on the virus phenotype. In contrast to wt SV5, rSV5-V/P N(100)D blocked IFN signaling in murine cells. Furthermore, rSV5-V/P N(100)D virus protein synthesis in BF cells continued for significantly longer periods than that for wt SV5. However, even in cells infected with rSV5-V/P N(100)D, there was a late, but significant, inhibition in virus protein synthesis. Nevertheless, there was an increase in virus yield from BF cells infected with rSV5-V/P N(100)D compared to wt SV5, demonstrating a clear selective advantage to SV5 in being able to block IFN signaling in these cells.
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PMID:Single amino acid substitution in the V protein of simian virus 5 differentiates its ability to block interferon signaling in human and murine cells. 1123 62

Interleukin-12 (IL-12) plays a critical role in modulating the function of T lymphocytes and natural killer cells. IL-12 has potent antitumor effects in animal models, mediated primarily by its ability to enhance cytolytic activity and secretion of interferon-gamma (IFN-gamma). Unfortunately, the antitumor effect of IL-12 has not been demonstrated in clinical trials. Repeated administration of IL-12 in humans results in decreasing levels of IFN-gamma secretion. To understand the mechanism underlying this loss of responsiveness, the effect of IL-12 on its own signaling in activated human T cells was examined. These experiments demonstrate that the level of the signal transducer and activator of transcription 4 (STAT4) protein, a critical IL-12 signaling component, is dramatically decreased 24 hours after IL-12 stimulation, whereas levels of STAT4 messenger RNA are not affected. The decrease of STAT4 protein appears to be due to specific degradation of phospho-STAT4, possibly through the proteasome degradation pathway. Decreased levels of STAT4 protein lead to decreased STAT4 DNA-binding activity and reduced proliferation and secretion of IFN-gamma. This down-regulation of STAT4 is specific for IL-12 signaling, presumably owing to the prolonged activation of STAT4 induced by IL-12. IFN-alpha stimulation, which leads to transient phosphorylation of STAT4, does not reduce the level of STAT4 protein. These findings provide new insights into the regulation of IL-12 signaling in human T cells, where IL-12 promotes T(H)1 responses, but persistent IL-12 stimulation may also limit this response. The cellular depletion of STAT4 following prolonged IL-12 stimulation may also explain the loss of responsiveness following the repeated administration of IL-12 in clinical trials. (Blood. 2001;97:3860-3866)
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PMID:Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation. 1138 27

Human parainfluenza type 2 virus (hPIV-2)-infected HeLa (HeLa-CA) cells and hPIV-2 V-expressing HeLa (HeLa-V) cells show high resistance to alpha/beta interferons (IFN-alpha/beta) irrespective of whether vesicular stomatitis virus or Sindbis virus is used as a challenge virus. When Sindbis virus is used, these cells show high susceptibility to human IFN-gamma. Furthermore, the multiplication of HeLa-V cells is not inhibited by IFN-alpha/beta. HeLa cells expressing the N-terminally truncated V protein show resistance to IFN-alpha/beta, showing that the IFN resistance determinant maps to the cysteine-rich V-specific domain. A complete defect of Stat2 is found in HeLa-CA and HeLa-V cells, whereas the levels of Stat1 expression are not significantly different among HeLa, HeLa-CA, HeLa-P, and HeLa-V cells, indicating that IFN-alpha/beta resistance of HeLa-CA and HeLa-V cells is due to a defect of Stat2. HeLa-SV41V cells show high resistance to all IFNs, and no expression of Stat1 can be detected. Stat2 mRNA is fully detected in HeLa-V cells. Stat2 was scarcely pulse-labeled in the HeLa-V cells, indicating that synthesis of Stat2 is suppressed or Stat2 is very rapidly degraded in HeLa-V cells. The V protein suppresses the in vitro translation of Stat2 mRNA more extensively than that of Stat1 mRNA. An extremely small amount of Stat2 can be detected in HeLa-V cells treated with proteasome inhibitors. The half-life of Stat2 is approximately 3.5 and 2 h in uninfected and hPIV-2-infected HeLa cells, respectively. This study shows that synthesis of Stat2 may be suppressed and Stat2 degradation is also enhanced in hPIV-2-infected HeLa and HeLa-V cells.
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PMID:High resistance of human parainfluenza type 2 virus protein-expressing cells to the antiviral and anti-cell proliferative activities of alpha/beta interferons: cysteine-rich V-specific domain is required for high resistance to the interferons. 1153 80

The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Proteasome activity and epitope production are altered by IFN-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. However, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. Here we show that the infection of mice with lymphocytic choriomeningitis virus or Listeria monocytogenes leads to an almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within 7 days. Proteasome replacements were markedly reduced in IFN-gamma(-/-) mice, but were only slightly affected in IFN-alphaR(-/-) and perforin(-/-) mice. The proteasome regulator PA28alpha/beta was up-regulated, whereas PA28gamma was reduced in the liver of lymphocytic choriomeningitis virus-infected mice. Proteasome replacements in the liver strongly altered proteasome activity and were unexpected to this extent, since an in vivo half-life of 12 days had been previously assigned to constitutive proteasomes in the liver. Our results suggest that during the peak phase of viral and bacterial elimination the antiviral cytotoxic T lymphocyte response is directed mainly to immunoproteasome-dependent T cell epitopes, which would be a novel parameter for the design of vaccines.
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PMID:Immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver. 1173 3

The hepatitis C virus (HCV) envelope protein E2 has been shown to accumulate in the lumen of the endoplasmic reticulum (ER) as a properly folded glycoprotein as well as large aggregates of misfolded proteins. In the present study, we have identified an additional unglycosylated species, with an apparent molecular mass of 38 kDa (E2-p38). In contrast to the glycosylated E2, E2-p38 is significantly less stable and is degraded through the proteasome pathway. Correspondingly, E2-p38 is found to be ubiquitinated. E2-p38 is localized mostly in the cytosol, in contrast to the glycosylated form, which is exclusively membrane associated. Alpha interferon (IFN-alpha) treatment or overexpression of the double-stranded RNA-activated protein kinase (PKR) significantly increased the stability of E2-p38, consistent with a previous report (D. R. Taylor, S. T. Shi, P. R. Romano, G. N. Barber, and M. M. Lai, Science 285:107-110, 1999) that E2 interacts with PKR and inhibits its kinase activity. Direct interaction between PKR and E2-p38, but not the glycosylated form of E2, was also observed. These results show that E2-p38 is the form of E2 that interacts with PKR in the cytosol and may contribute to the resistance of HCV to IFN-alpha. Thus, an ER protein can exist in the cytosol as an unglycosylated species and impair cellular functions.
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PMID:Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR. 1177 2

Hepatitis B virus (HBV) replication is inhibited in a noncytopathic manner by alpha/beta interferon (IFN-alpha/beta) and IFN-gamma. We demonstrate here that inhibitors of cellular proteasome activity can block this antiviral effect. These results suggest that a critical component of the IFN-induced antiviral response may be the proteasome-dependent degradation of viral or cellular proteins that are required for HBV replication.
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PMID:Inhibition of hepatitis B virus replication by interferon requires proteasome activity. 1188 82


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