Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells

Dirk Brenner; Markus Brechmann; Simone Roehling; Myriam Tapernoux; Thomas Mock; Dominic Winter; Wolf D. Lehmann; Friedemann Kiefer; Margot Thome; Peter H. Krammer; Ruediger Arnold

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Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells

机译：HPK1使CARMA1磷酸化对于T细胞中NF-κB激活至关重要

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Activation of the NF-κB pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-κB activation. Knock-down of HPK1 abrogates TCR-induced IKKβ and NF-κB activation, whereas active HPK1 leads to increased IKKβ activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-κB activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKCθ consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kB activation and IL-2 expression in CARMA1-def icient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-κB response upon TCR stimulation.

机译：诱导适应性免疫应答需要激活T细胞中的NF-κB通路。造血祖细胞激酶（HPK1）是T细胞受体（TCR）诱导的NF-κB激活的重要近端介质。敲低HPK1可以消除TCR诱导的IKKβ和NF-κB激活，而活跃的HPK1则可以提高T细胞中的IKKβ活性。然而，该过程的精确分子机制仍然难以捉摸。在这里，我们显示HPK1介导的NF-κB激活依赖于衔接蛋白CARMA1。 HPK1以TCR刺激依赖性方式与CARMA1相互作用，并使CARMA1的接头区域磷酸化。有趣的是，CARMA1中推定的HPK1磷酸化位点与已知的PKCθ共有位点不同。 CARMA1中残基S549，S551和S552的突变消除了HPK1在体外对CARMA1接头构建体的磷酸化作用。此外，CARMA1 S551A或S5549A / S551A点突变体未能恢复HPMA1介导的T细胞中HPK1介导的和TCR介导的NF-kB激活以及IL-2的表达。因此，我们确定HPK1为CARMA1特有的激酶，并建议HPK1介导的CARMA1磷酸化为调节TCR刺激时调节NF-κB反应的其他调节机制。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2009年第34期|14508-14513|共6页
作者
Dirk Brenner; Markus Brechmann; Simone Roehling; Myriam Tapernoux; Thomas Mock; Dominic Winter; Wolf D. Lehmann; Friedemann Kiefer; Margot Thome; Peter H. Krammer; Ruediger Arnold;
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作者单位

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M56 2C1;

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

Department of Biochemistry, University of Lausanne, 153, Chemin des Boveresses, 1066 Epalinges, Switzerland;

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

Molecular Structure Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Department of Pathology, Children's Hospital Boston, Enders Building, Room 1126, 300 Longwood Avenue, Boston, MA 02115;

Molecular Structure Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

Max-Planck-lnstitute for Molecular Biomedicine, Department of Vascular Cell Biology, Roentgenstrasse 20, 48149 Muenster, Germany;

Department of Biochemistry, University of Lausanne, 153, Chemin des Boveresses, 1066 Epalinges, Switzerland;

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
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关键词
CBM complex; IKK; TCR; PKC;

机译：煤层气综合体;IKK;TCR;PKC;

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专利

1. Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation. [J] . Matsumoto R, Wang D, Blonska M, Immunity . 2005,第6期

机译：CARMA1的磷酸化在T细胞受体介导的NF-κB活化中起关键作用。
2. Regulation of NF-κB Activation in T Cells via Association of the Adapter Proteins ADAP and CARMA1 [J] . Ricardo B. Medeiros, Brandon J. Burbach, Kristen L. Mueller, Science . 2007,第5825期

机译：通过衔接蛋白ADAP和CARMA1的关联调节T细胞中NF-κB的活化
3. CARMA1 Is Required for Akt-Mediated NF-κB Activation in T Cells [J] . Preeti Narayan, Brittany Holt, Richard Tosti, Molecular and Cellular Biology . 2006,第6期

机译：CARMA1是Akt介导的T细胞中NF-κB激活所必需的
4. Activation of MAPK and NF-κB induced by biomaterials in vascular endothelial cells [C] . Jiao Sun, Xinning Mu, Tingting Ding International Conference on Multifunctional Materials and Structures . 2008

机译：血管内皮细胞生物材料诱导MAPK和NF-κB的激活
5. Interaction of PKCbeta with CARMA1 mediates B cell receptor-induced NF-kappaB activation. [D] . Guo, Beichu. 2003

机译：PKCbeta与CARMA1的相互作用介导B细胞受体诱导的NF-κB活化。
6. Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells [O] . Dirk Brenner, Markus Brechmann, Simone Röhling, 2009

机译：HPK1使CARMA1磷酸化对于T细胞中NF-κB激活至关重要
7. Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells [O] . Brenner, Dirk, Brechmann, Markus, Röhling, Simone, 2009

机译：HPK1使CARMA1磷酸化对于T细胞中NF-κB激活至关重要

Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells

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