E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

Qiao, Guilin; Ying, Haiyan; Zhao, Yixia; Liang, Yanran; Guo, Hui; Shen, Huifeng; Li, Zhenping; Solway, Julian; Tao, Enxiang; Chiang, Y. Jeffrey; Lipkowitz, Stanley; Penninger, Josef; Langdon, Wallace Y.; Zhang, Jian

doi:10.1016/j.celrep.2014.01.012

Cited by 53 publications

(74 citation statements)

References 51 publications

(66 reference statements)

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“…These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation and tolerance. In strong support of this notion, Cblb −/− T cells are resistant to anergy induction in vitro and in vivo (17, 18), and Cblb −/− mice are highly susceptible to autoimmune/inflammatory diseases (12–14, 19). …”

Section: Introductionmentioning

confidence: 84%

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E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Zhao

Guo

Qiao

et al. 2015

The Journal of Immunology

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CD28 costimulation is essential for the development of Thymic-derived CD4+CD25+Foxp3+ regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. Here, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28−/− mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation, and together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28−/− T cells, the defective development of tTregs in Cd28−/− mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28−/− mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.

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Section: Introductionmentioning

confidence: 84%

“…Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, plays an important role in regulating T cell signaling threshold and T cell differentiation (10–12). Gene targeting in mice has shown that Cbl-b functions a gatekeeper involved in the maintenance of a balance between immunity and tolerance (13, 14).…”

Section: Introductionmentioning

confidence: 99%

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Zhao

Guo

Qiao

et al. 2015

The Journal of Immunology

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“…It is important to point out that the loss of STAT6 immunoreactivity was further supported by western blotting readouts showing the absence or greatly reduced levels of chimeric protein in two STAT6 immunohistochemistry-negative cases. Post-transcriptional mechanisms of STAT6 downregulation are known in hematological cell lineages and include CBL-B mediated ubiquitination followed by proteasome degradation in T-cells, 21 and the proteolytic generation of a shorter STAT6 isoform (65 kDa) lacking the COOH terminal transactivation domain in mast cells. 22 Similar mechanisms may be responsible for NAB2/STAT6 chimera downregulation and loss in dedifferentiated solitary fibrous tumors, in which the light cytoplasmic immunostaining in association with the decrease or loss of STAT6 nuclear labeling favor the ubiquitination-mediated mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14], and 10 as having dedifferentiated solitary fibrous tumors (nos. [15][16][17][18][19][20][21][22][23][24].…”

Section: Patients and Primary Tumorsmentioning

confidence: 99%

Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation

et al. 2015

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Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor. Modern Pathology (2015Pathology ( ) 28, 1074Pathology ( -1083 doi:10.1038/modpathol.2015 published online 29 May 2015 Solitary fibrous tumors are rare mesenchymal tumors (incidence o 1 per million) that were originally described on the pleurae but have subsequently been recognized at virtually all body sites. 1 The current classification includes usual, malignant and the recently described dedifferentiated variants. [1][2][3] The morphobiological features distinguishing the malignant and usual variants are hypercellularity, cell pleomorphism, necrosis and a mitotic index of 44/10 high-power fields. However,

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“…GRAIL knockout animals are highly susceptible to allergic inflammation and their naïve CD4+ T cells fail to appropriately degrade STAT6 after in vitro TCR stimulation 53 . Cbl-b also drives STAT6 polyubiquitylation and degradation 54 . Similar to Grail −/− animals, Cbl-b −/− animals are highly susceptible to induced allergic inflammation due to a Th2 and Th9 bias in their T cells.…”

Section: Th2 Cellsmentioning

confidence: 99%

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

Layman

Oliver

2016

The Journal of Immunology

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The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and GI tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4+ T cells can be recruited, including T helper cells known as Th1, Th2, and Th17, T follicular helper (Tfh) cells, and regulatory T cells (Tregs). These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. As these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts both levels and functions of effector fate-determining factors is ubiquitylation. This review will detail our current understanding of how ubiquitylation regulates CD4 T cell effector identity and function.

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E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

Cited by 53 publications

References 51 publications

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

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