TRIM27 is a new negative regulator of CD4 T cells and Mast cells.

TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。

基本信息

项目摘要

DESCRIPTION (provided by applicant): The K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of B, T, and mast cells. Our studies have found that T cell receptor (TCR) activation leads to activation of KCa3.1 by activating the class 2 phosphatidylinositol 3 kinase C2 Beta (PI3K-C2ß) leading to the generation of PI3P, which is required for the subsequent activation of a mammalian histidine kinase, Nucleoside Diphosphate Kinase B, that then activates KCa3.1. We identified the Tripartate Motif containing protein 27 (TRIM27) as a new negative regulator of PI3K-C2ß and KCa3.1. TRIM27 is a member of a large family of proteins characterized by the presence of a tripartite motif, consisting of a RING finger, B box, and coiled coil (CC) domains. In this proposal, we will determine the mechanisms whereby TRIM27 regulates PI3K-C2ß, its physiological significance, and subsequent role as a negative regulator of KCa3.1 in lymphocyte and mast cell activation in vitro and in vivo. We have evidence that TRIM27 functions an E3 ligase and ubiquitinates and inhibits PI3K-C2ß. To determine the mechanism(s) whereby TRIM27 regulates PI3K-C2ß and how this is affected by TCR activation, we will determine in SA1, (Ai) the type of TRIM27 mediated ubiquitination of PI3K-C2ß; (Aii) the lysine residues on TRIM27 and PI3K-C2ß that are ubiquitinated; and (Aiii) the regions or domains on TRIM27 and PI3K-C2ß that mediate their association. In 1B, we will determine: (Bi) if TRIM27 regulates TCR stimulated PI3K-C2ß's kinase activity and/or degradation, or whether (Bii) association of TRIM27 with PI3K-C2ß is affected by TCR stimulation; (Biii) whether TRIM27 is recruited to the immunological synapse (IS), its role in IS formation and/or the recruitment PI3K-C2ß to IS following TCR activation; (Biv) whether TRIM27 modulates the PI3P levels in activated T cells, or (Bv) whether TRIM27 autoubiquitination, or ubiquitination of PI3K-C2ß is modulated by TCR stimulation. In (C), the role of TRIM27 stimulated SUMOylation of PI3K-C2ß will be assessed. We have generated TRIM27-/- mice and have evidence that KCa3.1 channel activity and TCR- stimulated Ca2+ flux are increased in TRIM27-/- Th1 cells. In SA2 (A), we will extend these studies to other CD4 helper T cell subsets, and determine whether Th2, Th17, and Treg differentiation and/or function are altered in cells isolated from TRIM27-/- mice. In (B), we will determine the downstream signaling pathways regulated by TRIM27, and (C) whether TRIM27-/- mice are predisposed to autoimmune disease. In (D) we will undertake a nonbiased approach to identify other targets of TRIM27 ubiquitination and regulation We found that TRIM27 functions to negatively regulate FceR1 stimulated KCa3.1 channel activity and Ca2+ flux in mast cells. We will determine in SA3: (A) if PI3K-C2ß mediates FceR1 stimulated activation of KCa3.1 and whether this is modulated by TRIM27; (B) whether effectors functions of TRIM27-/- mast cells are increased; (3C) the signaling pathways regulated by TRIM27 in mast cells, and/or (3D) whether TRIM27-/- mice have an increased anaphylactic response to both passive cutaneous and systemic anaphylaxis.
描述(申请人提供):K+通道KCa3.1是钙离子内流以及随后激活B、T和肥大细胞所必需的。我们的研究发现,T细胞受体(TCR)的激活导致KCa3.1的激活,途径是激活2类磷脂酰肌醇3激酶C2 Beta(PI3K-C2?),从而产生PI3P,这是随后激活哺乳动物组氨酸激酶-二磷酸核苷激酶B所必需的,然后激活KCa3.1。我们鉴定了含有蛋白27的三部分基序(TRIM27)是PI3K-C2?和KCa3.1的一个新的负调控因子。TRIM27是一个大的蛋白质家族的成员,其特征是存在一个由环指、B盒和卷曲线圈(CC)结构域组成的三部分基序。在这项建议中,我们将确定TRIM27调节PI3K-C2?的机制、其生理意义,以及在体外和体内作为KCa3.1负调节因子在淋巴细胞和肥大细胞激活中的作用。我们有证据表明,TRIM27具有E3连接酶的功能,泛素化并抑制PI3K-C2?为了确定TRIM27调节PI3K-C2ü的机制(S)以及TCR激活如何影响这一机制,我们将在SA1中确定(AI)TRIM27介导的PI3K-C2?泛素化的类型;(Aii)TRIM27和PI3K-C2?上泛素化的赖氨酸残基;以及(Aiii)TRIM27和PI3K-C2上介导它们结合的区域或结构域。在1B中,我们将确定:(Bi)TRIM27是否调节TCR刺激的PI3K-C2?S激酶的活性和/或降解,或者TRIM27与PI3K-C2?的关联是否受到TCR刺激的影响;(Biii)TRIM27是否被招募到免疫突触(IS),它在免疫突触(IS)的形成和/或TCR激活后PI3K-C2?的募集中的作用;(Biv)TRIM27是否调节激活的T细胞中PI3P的水平,或者(BV)TRIM27是否调节TCR激活的T细胞中PI3P水平,或者PI3K-C2?的泛素化是否受到TCR刺激的调节。在(C)中,将评估TRIM27刺激的PI3K-C2?的SUMO化的作用。我们已经建立了TRIM27-/-小鼠,并有证据表明,在TRIM27-/-Th1细胞中,KCa3.1通道活性和TCR刺激的钙通量增加。在SA2(A)中,我们将把这些研究扩展到其他CD4辅助T细胞亚群,并确定从TRIM27-/-小鼠分离的细胞中Th2、Th17和Treg的分化和/或功能是否发生改变。在(B)中,我们将确定受TRIM27调控的下游信号通路,以及(C)TRIM27-/-小鼠是否易患自身免疫性疾病。在(D)中,我们将采取一种无偏见的方法来确定TRIM27泛素化和调控的其他靶点。我们发现,TRIM27具有负调控FceR1刺激的肥大细胞KCa3.1通道活性和钙离子通量的功能。我们将在SA3中确定:(A)PI3K-C2是否介导FceR1刺激的KCa3.1激活以及这是否受TRIM27的调节;(B)TRIM27-/-肥大细胞的效应功能是否增加;(3C)TRIM27-/-肥大细胞中的信号通路是否由TRIM27调节;和/或(3D)TRIM27-/-小鼠对被动皮肤和全身过敏反应是否增加。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1.
  • DOI:
    10.1091/mbc.e13-04-0180
  • 发表时间:
    2014-04
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Cai X;Srivastava S;Surindran S;Li Z;Skolnik EY
  • 通讯作者:
    Skolnik EY
Nucleoside Diphosphate Kinase B Regulates Angiogenesis Through Modulation of Vascular Endothelial Growth Factor Receptor Type 2 and Endothelial Adherens Junction Proteins
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EDWARD Y SKOLNIK其他文献

EDWARD Y SKOLNIK的其他文献

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{{ truncateString('EDWARD Y SKOLNIK', 18)}}的其他基金

Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
  • 批准号:
    10462701
  • 财政年份:
    2021
  • 资助金额:
    $ 32.96万
  • 项目类别:
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
  • 批准号:
    10629396
  • 财政年份:
    2021
  • 资助金额:
    $ 32.96万
  • 项目类别:
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
  • 批准号:
    10298937
  • 财政年份:
    2021
  • 资助金额:
    $ 32.96万
  • 项目类别:
Histidine Phosphorylation in Mammals: Regulation, Protein Targets, and Biology
哺乳动物中的组氨酸磷酸化:调节、蛋白质靶点和生物学
  • 批准号:
    10395477
  • 财政年份:
    2019
  • 资助金额:
    $ 32.96万
  • 项目类别:
Histidine Phosphorylation in Mammals: Regulation, Protein Targets, and Biology
哺乳动物中的组氨酸磷酸化:调节、蛋白质靶点和生物学
  • 批准号:
    10152661
  • 财政年份:
    2019
  • 资助金额:
    $ 32.96万
  • 项目类别:
Identification and characterization of a novel mammalian histidine phosphatase that negatively regulates CD4 T cells
负调节 CD4 T 细胞的新型哺乳动物组氨酸磷酸酶的鉴定和表征
  • 批准号:
    9330534
  • 财政年份:
    2016
  • 资助金额:
    $ 32.96万
  • 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
  • 批准号:
    8667953
  • 财政年份:
    2013
  • 资助金额:
    $ 32.96万
  • 项目类别:
New Signaling pathways that positively and negatively regulate CD4 T cells via th
通过 th 正向和负向调节 CD4 T 细胞的新信号通路
  • 批准号:
    8742789
  • 财政年份:
    2013
  • 资助金额:
    $ 32.96万
  • 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
  • 批准号:
    8541082
  • 财政年份:
    2012
  • 资助金额:
    $ 32.96万
  • 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
  • 批准号:
    8218480
  • 财政年份:
    2012
  • 资助金额:
    $ 32.96万
  • 项目类别:

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