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)

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

Proteasomes play a major role in non-lysosomal proteolysis and also in the processing of proteins for presentation by the MHC class I pathway. In animal cells they exist in several distinct molecular forms which contribute to the different functions. 26S proteasomes contain the core 20S proteasome together with two 19S regulatory complexes. Alternatively, PA28 complexes can bind to the ends of the 20S proteasome to form PA28-proteasome complexes and PA28-proteasome-19S hybrid complexes have also been described. Immunoproteasome subunits occur in 26S proteasomes as well as in PA28-proteasome complexes. We have found differences in the subcellular distribution of the different forms of proteasomes. The gamma-interferon inducible PA28 alpha and beta subunits are predominantly located in the cytoplasm, while 19S regulatory complexes (present at significant levels only in 26S complexes) are present in the nucleus as well as in the cytoplasm. Immunoproteasomes are greatly enriched at the endoplasmic reticulum (ER) where they may facilitate the generation of peptides for transport into the lumen of the ER. We have also investigated the effects of gamma-interferon on the levels and subcellular distribution of inducible subunits and regulator subunits. In each case gamma-interferon was found to increase the level but not to alter the distribution. Several subunits of proteasomes are phosphorylated including alpha subunits C8 (alpha7) and C9 (alpha3), and ATPase subunit S4 (rpt2). Our studies have shown that gamma-interferon treatment decreases the level of phosphorylation of proteasomes. We have investigated the role of phosphorylation of C8 by casein kinase II by site directed mutagenesis. The results demonstrate that phosphorylation at either one of the two sites is essential for the association of 19S regulatory complexes and that the ability to undergo phosphorylation at both sites gives the most efficient incorporation of C8 into the 26S proteasome.
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PMID:Regulation of proteasome complexes by gamma-interferon and phosphorylation. 1129 98

The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.
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PMID:The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. 1131 18

Type I interferon (IFN) induces antiviral responses through the activation of the ISGF3 transcription factor complex that contains the subunit proteins STAT1, STAT2, and p48/ISGF3 gamma/IRF9. The ability of some human paramyxoviruses to overcome IFN actions by specific proteolysis of STAT proteins has been examined. Infection of cells with type 2, but not type 1 or type 3 human parainfluenza virus (HPIV) leads to a loss of cellular STAT2 protein. Expression of a single HPIV2 protein derived from the V open reading frame blocks IFN-dependent transcriptional responses in the absence of other viral proteins. The loss of IFN response is due to V-protein-induced proteolytic degradation of STAT2. Expression of HPIV2 V causes the normally stable STAT2 protein to be rapidly degraded, and this proteolytic activity can be partially alleviated by proteasome inhibition. No V-protein-specific effects on STAT2 mRNA levels were observed. The results indicate that the V protein of HPIV2 is sufficient to recognize and target a specific cellular transcription factor for destruction by cellular machinery.
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PMID:The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. 1133 48

Hepatitis C virus (HCV) infection takes a chronic course in the majority of patients. The mechanisms underlying the evasion of the host immune response and viral persistence are poorly understood. In this context, we investigated interactions of HCV proteins with major histocompatibility complex (MHC) class I processing and presentation pathways using cell lines that allow the tetracycline-regulated expression of viral structural and nonstructural proteins. These well-characterized inducible cell lines were found to efficiently process and present endogenously synthesized HCV proteins via MHC class I. Functional MHC class I cell-surface expression and intracellular proteasome activity were not affected by the expression of HCV proteins. These results suggest that viral evasion of the host immune response does not involve interactions of HCV with MHC class I processing and presentation. Other mechanisms, such as interference with the interferon system, may be operative in HCV infection, leading to viral persistence.
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PMID:Expression of hepatitis C virus proteins does not interfere with major histocompatibility complex class I processing and presentation in vitro. 1134 57

The proteasome activator PA28 is an interferon-gamma-inducible complex made up of two related subunits, named PA28 alpha and PA28 beta, with approximately 50% amino acid sequence identity. Accumulated evidence indicates that binding of this complex to the 20S proteasome enhances the generation of class I-binding peptides. Previously, we showed that the genes coding for PA28 alpha and PA28 beta, designated Psme1 and Psme2, respectively, are located approximately 6 kb apart with their 3' ends pointing toward each other on mouse Chromosome 14. In the present study, we sequenced the regions adjacent to Psme1 and Psme2. In a contiguous stretch of approximately 35 kb, we identified six genes arranged in the following order: Cg10671-like (a gene similar to Drosophila CG10671)-Psme1-Cgi112 (a ubiquitously expressed gene with no known function)-Psme2-Flj10111 (a gene coding for a protein with two RING finger domains)-Isgf3g (an interferon-gamma-inducible gene coding for an interferon-dependent, positive-acting transcription factor 3 gamma). Interestingly, the 3' untranslated region of Psme1 overlaps with that of Cgi112 by 7 bp. Database analysis indicates that the corresponding human genes also overlap by up to 7 bp in their 3' untranslated regions. The 5' end of the mouse, but not the human, gene coding for PA28 beta undergoes alternative splicing that is predicted to alter the N-terminal amino acid sequence. Comparison of the mouse sequence with a human draft sequence deposited in the NCBI database revealed that the overall organization of the region coding for the interferon-gamma-inducible proteasome activator is conserved between human and mouse.
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PMID:Nucleotide sequence analysis of the approximately 35-kb segment containing interferon-gamma-inducible mouse proteasome activator genes. 1134 88

Cytokine induced gene expression is mediated through the ligand-dependent activation of the janus kinase (jak)/signal transducer and activator of transcription (STAT) signal transduction pathway. The ubiquitin proteasome pathway functions in the controlled degradation of cellular proteins, and regulates cytokine signal transduction through the degradation of specific signaling components. Interferon (IFN) treatment induces genes that function in ubiquitin conjugation, suggesting a reciprocal regulation of proteasome activity and IFN action; however, a role for the proteasome in IFN-alpha-induced gene expression has not been examined. In this report, we find that proteasome inhibitors markedly reduce the induction of interferon-stimulated-gene 15 (ISG15), ISG43, and STAT1 by IFN-alpha and double-stranded RNA (dsRNA). The reduction in gene expression by proteasome inhibitors was dose-dependent, and was specific for ISGs. Neither STAT1 phosphorylation nor ISGF-3 activation was affected by proteasome inhibition at early times post-IFN treatment. Cycloheximide treatment diminished the effect of proteasome inhibitors on ISG induction, implicating an IFN/dsRNA-induced protein in this activity. These findings demonstrate that a functional proteasome is required for optimal ISG induction, and are consistent with a model in which IFN and dsRNA induce a proteasome-sensitive repressor of ISG expression.
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PMID:Involvement of proteasomes in gene induction by interferon and double-stranded RNA. 1144 4

In cervical carcinomas abnormalities in the MHC class I surface expression are a frequent event, which are often associated with the deficient expression of the peptide transporter subunit TAP1 thereby resulting in impaired T cell response. In order to understand the role of other components of the MHC class I antigen processing machinery (APM) in the immune escape, 16 surgically removed primary cervical carcinoma lesions were analyzed for their mRNA expression of the heterodimeric peptide transporter TAP, the constitutive and interferon (IFN)-gamma inducible proteasome subunits and their activators PA28alpha/beta, various chaperones as well as MHC class I antigens. High expression levels of all APM components were detected in normal cervical tissue, whereas 15/16 of cervical carcinoma lesions exhibited an impaired expression of at least one APM component, including the proteasome subunits, their activators PA28alpha/beta, the peptide transporter subunits TAP1 and TAP2, different chaperones, HLA class I heavy chains and beta2-microglobulin (beta2-m). In particular, calnexin expression was strongly downregulated in 69% of cervical cancer lesions analyzed. Such abnormalities were neither associated with a specific human papilloma virus (HPV) or HLA class I phenotype nor with tumor grading and staging. Analysis of five cervical carcinoma cell lines demonstrated a reduced MHC class I surface expression due to deficient expression and function of TAP, LMP subunits or specific HLA-alleles which could be mostly corrected by IFN-gamma treatment. The high frequency of abnormalities of APM component expression together with their potential negative influence on T cell-mediated immune recognition emphasize the need to evaluate the antigen processing pathway in cervical carcinoma patients, particularly in those selected for T-cell-based immunotherapies.
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PMID:Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. 1171 91

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

Proteasomes play a major role in intracellular protein degradation and have been implicated in apoptosis. In this study we have investigated proteasome activity and the effects of inhibition of proteasomes or modulation of proteasome complexes on staurosporine-induced apoptosis in COS-7 cells. Staurosporine treatment of COS-7 cells had little direct effect on proteasome activity and did not cause dissociation of 26S proteasomes. There was also no major redistribution of proteasomes accompanying apoptosis in COS-7 cells. However, when the cells were pretreated with proteasome inhibitors, both the caspase 3 activity of the cells and the percentage of apoptotic cells measured by the TUNEL assay were reduced compared to staurosporine-treated cells, which had no inhibitor added. Proteasome inhibitors were also found to reduce the activation of caspase 3 in living cells which was assayed using a FRET-based method. However, proteasome inhibitors did not prevent some of the morphological changes associated with staurosporine-induced apoptosis. Pretreatment of cells with gamma-interferon, which increases immunoproteasomes and PA28 complexes and reduces 26S proteasome levels, had an antiapoptotic effect. These results are consistent with a role for 26S proteasomes in regulating the activation of caspase 3 through the degradation of key regulatory proteins.
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PMID:Treatment of COS-7 cells with proteasome inhibitors or gamma-interferon reduces the increase in caspase 3 activity associated with staurosporine-induced apoptosis. 1179 72


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