文章基本信息

标题：Phosphorylation of CARMA1 by HPK1 is critical for NF-κB activation in T cells
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作者：Dirk Brenner ; Markus Brechmann ; Simone Röhling 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：34
页码：14508-14513
DOI：10.1073/pnas.0900457106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Activation of the NF-{kappa}B 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-{kappa}B activation. Knock-down of HPK1 abrogates TCR-induced IKK{beta} and NF-{kappa}B activation, whereas active HPK1 leads to increased IKK{beta} activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-{kappa}B 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 PKC{theta} 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-{kappa}B activation and IL-2 expression in CARMA1-deficient 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-{kappa}B response upon TCR stimulation.
关键词：CBM complex ; IKK ; TCR ; PKC