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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cbl proteins have RING finger-dependent ubiquitin ligase (E3) activity that is essential for down-regulation of tyrosine kinases. Here we establish that two WW domain HECT E3s, Nedd4 and Itch, bind Cbl proteins and target them for proteasomal degradation. This is dependent on the E3 activity of the HECT E3s but not on that of Cbl. Consistent with these observations, in cells expressing the epidermal growth factor receptor, Nedd4 reverses Cbl-b effects on receptor down-regulation, ubiquitylation, and proximal events in signaling. Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation. These findings establish that RING finger E3s can be substrates, not only for autoubiquitylation but also for ubiquitylation by HECT E3s and suggest an additional level of regulation for Cbl substrates including protein-tyrosine kinases.
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PMID:WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. 1290 74

Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca(2+)-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.
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PMID:Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. 1498 8

Ubiquitin (Ub)-protein conjugation represents a novel means of posttranscriptional modification in a proteolysis-dependent or -independent manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer reactions by recognizing and catalyzing Ub conjugation to specific protein substrates. The E3s, which can be generally classified into HECT-type and RING-type families, are involved in the regulation of many aspects of the immune system, including the development, activation, and differentiation of lymphocytes, T cell-tolerance induction, antigen presentation, immune evasion, and virus budding. E3-promoted ubiquitination affects a wide array of biological processes, such as receptor downmodulation, signal transduction, protein processing or translocation, protein-protein interaction, and gene transcription, in addition to proteasome-mediated degradation. Deficiency or mutation of some of the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as autoimmunity, malignancy, and inflammation. This review discusses our current understanding of E3 Ub ligases in both innate and adaptive immunity. Such knowledge may facilitate the development of novel therapeutic approaches for immunological diseases.
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PMID:Ubiquitin ligases and the immune response. 1503 75

E3 ubiquitin ligases have emerged as key molecular regulators of immune cell function. Three families of proteins with ubiquitin ligase activity have been described (the HECT, RING and U-box proteins), and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. This review will discuss the relationship between the ubiquitination of select components of the antigen-sensing signaling apparatus in T cells and the development and maintenance of the clonal anergy state.
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PMID:E3 ubiquitin ligases as T cell anergy factors. 1533 84

A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.
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PMID:Up-regulation of gene related to anergy in lymphocytes is associated with Notch-mediated human T cell suppression. 1747 42

The ubiquitination system comprises a highly specific and regulated post-translational mechanism by which the immune response can be modulated, setting the balance between immunity and tolerance. Proteolysis dependent and independent mechanisms have been implicated. Particularly, the role of ubiquitin ligases as modulators of central and peripheral tolerance has brought attention to this system as one of the key elements of a complex regulatory network designed to maintain an active surveillance system. Cbl-b, GRAIL and Itch are the main E3 ligases, considered as negative regulators of the immune response as part of the genetic program induced by the calcium/calcineurin pathway. Other key signaling pathways for the immune response, such as the NF-kappaB and TGF-beta signaling are prone to be modulated by these ubiquitin ligases. Diverse mechanisms have been implicated in the development of anergy associated to E3 ligases, among these, the setting for TCR responsiveness and repression of cytokine transcription are best well characterized. Also, a role as inductors of regulatory T cells has been evidenced for Cbl-b and GRAIL. The defective expression of some of these E3 ligases has been related to the development of autoimmune disease, in experimental murine and human models, remarking its possible pathogenic role.
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PMID:Ubiquitination system and autoimmunity: the bridge towards the modulation of the immune response. 1829 31

Abrogating tolerance against unidentified antigens is a critical step in the pathogenesis of ulcerative colitis (UC). T cell anergy, one of the main mechanisms of tolerance, has been shown to be induced by E3 ubiquitin ligases, such as gene related to anergy in lymphocytes (GRAIL), Itch, and c-Cbl in mice. However, it is not well known whether these E3 ligases play roles in human diseases. The pathophysiological role of the E3 ligases in patients with UC was investigated. At first, the expression of GRAIL, Itch, and c-Cbl in human anergic T cells was analyzed by quantitative RT-PCR and Western immunoblotting. Next, the mRNA expression of the E3 ligases was analyzed in peripheral CD4+ T cells of 20 patients with UC and 10 healthy volunteers (HV). mRNA expression was analyzed in patients with active UC before and after treatment with prednisolone and leukocytapheresis. Anergic human CD4+ T cells expressed significantly higher levels of GRAIL, Itch, and c-Cbl than nonanergic cells. GRAIL expression was significantly higher in patients with UC in remission than in patients with active disease and in HV (P < 0.01). The level of GRAIL expression was also significantly increased in patients with active disease whose clinical activity index scores improved after treatment (P < 0.05). There were no significant differences in Itch and c-Cbl expression among patients with active UC, patients with UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.
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PMID:Upregulation of GRAIL is associated with remission of ulcerative colitis. 1846 99

Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4(+/+) and Nedd4(-/-) fetal liver chimeras. Nedd4(-/-) T cells developed normally but proliferated less, produced less interleukin 2 and provided inadequate help to B cells. Nedd4(-/-) T cells contained more of the E3 ubiquitin ligase Cbl-b, and Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation. Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells. We propose that Nedd4 and Itch ubiquitinate distinct target proteins in vivo.
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PMID:Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. 1893 80

EGF-mediated stimulation of the EGF receptor activates a plethora of signaling cascades followed by receptor down regulation. Preventing down regulation leads to increased mitogenic signaling and potentially, cancer. Cbl and Endophilin are two key proteins required for EGF receptor down regulation and both become ubiquitylated and subject to proteasome-mediated degradation following EGF activation, providing a negative feedback loop for EGF receptor down regulation. The mechanism of this pathway is unknown. Here, we demonstrate that treatment of cells with EGF leads to JNK-dependent phosphorylation of the ubiquitin ligase Itch, stimulating Itch ligase activity. EGF-stimulated JNK activation causes an increased interaction between Itch and the de-ubiquitylating enzyme FAM, limiting the influence of Itch auto-ubiquitylation on its own degradation. Finally, JNK activation stimulates the association of Itch with its substrates. These effects combine to cause increased ubiquitylation of Itch substrates including Endophilin and Cbl, resulting in the proteasome-dependent down regulation of these key trafficking proteins. Thus, Itch is a key regulatory locus for EGF receptor degradation.
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PMID:Reciprocal regulation of the ubiquitin ligase Itch and the epidermal growth factor receptor signaling. 1934 94

E3 ubiquitin ligases, which target specific molecules for proteolytic destruction, have emerged as key regulators of immune functions. Several E3 ubiquitin ligases, including c-Cbl, Cbl-b, GRAIL, Itch, and Nedd4, have been shown to negatively regulate T-cell activation. Here, we report that the HECT-type E3 ligase AIP2 positively regulates T-cell activation. Ectopic expression of AIP2 in mouse primary T cells enhances their proliferation and interleukin-2 production by suppressing the apoptosis of T cells. AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. Suppression of AIP2 expression by small RNA interference upregulates EGR2, inhibits EGR2 ubiquitination and FasL expression, and enhances the apoptosis of T cells. Therefore, AIP2 regulates activation-induced T-cell death by suppressing EGR2-mediated FasL expression via the ubiquitin pathway.
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PMID:The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination. 1965


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