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)

Bone marrow failure has been regarded as one of the triad of clinical manifestations of paroxysmal noctumal hemoglobinuria (PNH), and PNH in turn has been described as a late clonal disease evolving in patients recovering from aplastic anemia. Better understanding of the pathophysiology of both diseases and improved tests for cell surface glycosylphosphatidylinositol (GPI)-linked proteins has radically altered this view. Flow cytometry of granulocytes shows evidence of an expanded PNH clone in a large proportion of marrow failure patients at the time of presentation: in our large NIH series, about 1/3 of over 200 aplastic anemia cases and almost 20% of more than 100 myelodysplasia cases. Clonal PNH expansion (rather than bone marrow failure) is strongly linked to the histocompatability antigen HLA.-DR2 in all clinical varieties of the disease, suggesting an immune component to its pathophysiology. An extrinsic mechanism of clonal expansion is also more consistent with knock-out mouse models and culture experiments with primary cells and cell lines, which have failed to demonstrate an intrinsic proliferative advantage for PNH cells. DNA chip analysis of multiple paired normal and PIG-A mutant cell lines and lymphoblastoid cells do not show any consistent differences in levels of gene expression. In aplastic anemia/PNH there is surprisingly limited utilization of the V-beta chain of the T cell receptor, and patients' dominant T cell clones, which are functionally inhibitory of autologous hematopoiesis, use identical CDR3 regions for antigen binding. Phenotypically normal cells from PNH patients proliferate more poorly in culture than do the same patient's PNH cells, and the normal cells are damaged as a result of apoptosis and overexpress Fas. Differences in protein degradation might play a dual role in pathophysiology, as GPI-linked proteins lacking an anchor would be predicted to be processed by the proteasome machinery and displayed in a class I H.A. context, in contrast to the normal pathway of cell surface membrane recycling, lysosomal degradation, and presentation by class II HLA. The strong relationship between a chronic, organ-specific immune destructive process and the expansion of a single mutant stem cell clone remains frustratingly enigmatic but likely to be the result of interesting biologic processes, with mechanisms that potentially can be extended to the role of inflammation in producing premalignant syndromes.
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PMID:The relationship of aplastic anemia and PNH. 1243 Sep 20

The immunosuppressive agent cyclosporin A (CsA), which interferes with signal transduction pathways leading to cytokine gene transcription in activated T cells, was investigated regarding its ability to induce apoptosis in T cells undergoing cell cycle progression and activation. In Jurkat and peripheral CD4+ T cells, CsA was found to markedly induce apoptosis at the G0 phase of the cell cycle. Susceptibility to CsA-induced apoptosis progressively decreased during cell cycle progression to the S and G2/M phase, and subsequent T cell receptor- and mitogen-mediated activation totally abrogated CsA-induced apoptosis. Because CsA is an inhibitor of the chymotryptic peptidase activity of the proteasome, susceptibility to apoptosis induced by the proteasome inhibitor lactacystin was investigated under the same conditions. A progressive increase of the susceptibility of T cells to lactacystin-induced apoptosis during cell cycle progression and activation was demonstrated. Intracellular protein levels of the cyclin-dependent kinase inhibitor p27(Kip1)decreased from the G0 to G2/M phase and from the cycling to the activation state, but remained unchanged during the induction of apoptosis by CsA and lactacystin, suggesting a role of p27(Kip1)in the regulation of susceptibility to apoptosis during cell cycle progression and activation. Inhibition of CsA- but not lactacytin-induced apoptosis by overexpression of Bcl-2 in Jurkat T cells revealed that CsA and proteasome inhibitors activate different apoptotic pathways, while both CsA- and lactacystin-induced apoptosis were found to be dependent on caspase activation and independent of the FasL/Fas system. The results show that T cells can progressively regulate their susceptibility to apoptosis during cell cycle progression and activation in a stimulus-dependent manner, and suggest that lactacystin, but not CsA, is able to deplete activated T cells by apoptosis, a mechanism deemed necessary for the induction of allograft tolerance.
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PMID:Cell cycle- and activation-dependent regulation of cyclosporin A-induced T cell apoptosis. 1452 16

After specific activation, CD8+ cytotoxic T lymphocytes (CTLs) enter a refractory state termed activation-induced nonresponsiveness (AINR) that is characterized by the inability of T cells to respond to a secondary stimulus. Here, we show that T cell receptor triggering results in rapid degradation of the src-family protein kinase lck through a mechanism that is proteasome- and lysosome-independent, sensitive to cysteine protease inhibitors, and distinct from the pathways involved in degradation of ZAP-70 kinase or zeta-chain of the CD3 complex. Pharmacologic blockade of lck degradation, as well as transfection of refractory cells with an lck expression vector, increased responsiveness of CTLs to repeated antigenic challenge. The development or maintenance of AINR was not affected by exogenously added IL-2, whereas IL-15 or IFN-alpha restored both lck expression and responsiveness of preactivated CTLs. Our results suggest that lck degradation plays an important role in the development of AINR in human CTLs and that this condition can be reverted by pharmacologic agents or lymphokines that prevent lck degradation or induce its expression.
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PMID:Regulation of lck degradation and refractory state in CD8+ cytotoxic T lymphocytes. 1595 29

Differentiation of naive CD4 T cells into Th2 cells requires protein expression of GATA3. Interleukin-4 induces STAT6 activation and subsequent GATA3 transcription. Little is known, however, on how T cell receptor-mediated signaling regulates GATA3 and Th2 cell differentiation. Here we demonstrated that T cell receptor-mediated activation of the Ras-ERK MAPK cascade stabilizes GATA3 protein in developing Th2 cells through the inhibition of the ubiquitin-proteasome pathway. Mdm2 was associated with GATA3 and induced ubiquitination on GATA3, suggesting its role as a ubiquitin-protein isopeptide ligase for GATA3 ubiquitination. Thus, the Ras-ERK MAPK cascade controls GATA3 protein stability by a post-transcriptional mechanism and facilitates GATA3-mediated chromatin remodeling at Th2 cytokine gene loci leading to successful Th2 cell differentiation.
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PMID:Ras-ERK MAPK cascade regulates GATA3 stability and Th2 differentiation through ubiquitin-proteasome pathway. 1597 24

Current evidences indicate that T cells use protein sorting and degradation to control duration and specificity of T cell receptor (TcR) signalling, including the CD3zeta chain which is ubiquitinated upon TcR triggering. In a previous study, we showed that the Linker of activated T cells (LAT) is present at the plasma membrane and in transferrin-labelled intracellular compartments also containing the CD3zeta chain. Here we show that LAT protein levels are tightly regulated in Jurkat lymphoid T cells likely involving proteasome-dependent degradation, recycling through trans-Golgi/endosome compartments and clathrin-dependent internalisation. We further identify a novel post-translational modification of LAT by ubiquitination that is likely to influence LAT protein stability, intracellular localisation and/or recycling. Our results provide novel molecular and regulatory insights into the function of LAT adapter protein in T cell signalling.
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PMID:Evidences for ubiquitination and intracellular trafficking of LAT, the linker of activated T cells. 1623 70

Palmitoylation is a protein modification for trafficking to lipid raft. Without palmitoylation, linker for activation of T cells (LAT), an adaptor molecule mediating T cell receptor signaling, is unable to localize in lipid rafts and to mediate T cell activation. We here show a novel role for palmitoylation in LAT trafficking to the plasma membrane and in the stability of the LAT protein. The human LAT mutant lacking palmitoylation was unable to traffic to the plasma membrane despite the presence of transmembrane portion. The mouse LAT mutant lacking palmitoylation was unstable and susceptible to degradation via the proteasome pathway. The human LAT mutant became unstable when the extracellular portion was swapped for that from mouse, indicating that both palmitoylation and the extracellular portion regulate the stability of LAT. These results suggest that palmitoylation has an important role in trafficking to the plasma membrane and the stability of LAT.
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PMID:Palmitoylation of LAT contributes to its subcellular localization and stability. 1646 Jun 87

Antigen recognition by the T cell receptor (TCR) elicits several intracellular signaling cascades, one of which activates the transcription factor NF-kappaB through IkappaB kinases (IKK). NF-kappaB regulates lymphocyte differentiation, proliferation, and apoptosis; thus, tight temporal control of its activation is required to prevent harmful immune cell dysregulation. Although considerable insight into the IKK and NF-kappaB activation process has emerged, less is known about the temporal regulation and termination of immunoreceptor signaling. Two recent studies have revealed that the scaffold protein Bcl10--which, together with CARMA1 and Malt1, forms the TCR-induced IKK-activating CBM complex--is a negative feedback substrate for IKK. IKKbeta initially contributes to CBM formation--which is required for full IKK activation--and then, through carboxyl-terminal Bcl10 phosphorylation, disrupts this structure to terminate signaling. IKK triggers Bcl10 degradation by the ubiquitin-proteasome system through phosphorylation of Bcl10 at other sites. Thus, inactivation through negative feedback mechanisms is an intrinsic property of the TCR-induced NF-kappaB pathway.
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PMID:Striking back at the activator: how IkappaB kinase terminates antigen receptor responses. 1747 8

CYLD is a protein with tumor suppressor properties which was originally discovered associated with cylindromatosis, an inherited cancer exclusively affecting the folicullo-sebaceous-apocrine unit of the epidermis. CYLD exhibits deubiquitinating activity and acts as a negative regulator of NF-kappaB and JNK signaling through its interaction with NEMO and TRAF2. Recent data suggest that this is unlikely to be its unique function in vivo. CYLD has also been shown to control other seemingly disparate cellular processes, such as proximal T cell receptor signaling, TrkA endocytosis and mitosis. In each case, this enzyme appears to act by regulating a specific type of polyubiquitination, K63 polyubiquitination, that does not result in recognition and degradation of proteins by the proteasome but instead controls their activity through diverse mechanisms.
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PMID:Tumor suppressor CYLD: negative regulation of NF-kappaB signaling and more. 1819 68

The nature of crosspriming immunogens for CD8(+) T cell responses is highly controversial. By using a panel of T cell receptor-like antibodies specific for viral peptides bound to mouse D(b) major histocompatibility complex class I molecules, we show that an exceptional peptide (PA(224-233)) expressed as a viral minigene product formed a sizeable cytosolic pool continuously presented for hours after protein synthesis was inhibited. PA(224-233) pool formation required active cytosolic heat-shock protein 90 but not ER g96 and uniquely enabled crosspriming by this peptide. These findings demonstrate that exceptional class I binding oligopeptides that escape proteolytic degradation are potent crosspriming agents. Thus, the feeble immunogenicity of natural proteasome products in crosspriming can be attributed to their evanescence in donor cells and not an absolute inability of cytosolic oligopeptides to be transferred to and presented by professional antigen-presenting cells.
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PMID:The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. 1854 99

The differentiation of naive CD4 T cells into Th2 cells requires the T cell receptor-mediated activation of the ERK MAPK cascade. Little is known, however, in regard to how the ERK MAPK cascade regulates Th2 cell differentiation. We herein identified Gfi1 (growth factor independent-1) as a downstream target of the ERK MAPK cascade for Th2 cell differentiation. In the absence of Gfi1, interleukin-5 production and the change of histone modification at the interleukin-5 gene locus were severely impaired. Furthermore, the interferon gamma gene showed a striking activation in the Gfi1(-/-) Th2 cells. An enhanced ubiquitin/proteasome-dependent degradation of GATA3 protein was observed in Gfi1(-/-) Th2 cells, and the overexpression of GATA3 eliminated the defect of Th2 cell function in Gfi1-deficient Th2 cells. These data suggest that the T cell receptor-mediated induction of Gfi1 controls Th2 cell differentiation through the regulation of GATA3 protein stability.
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PMID:Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation. 1870 59


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