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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappa B activation and cytokine production
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Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappa B activation and cytokine production

机译：Bcl10和Malt1控制溶血磷脂酸诱导的NF-κB活化和细胞因子的产生

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摘要

Lysophosphatidic acid (LPA) is a potent bioactive phospholipid that stimulates a variety of cellular responses by acting on cognate G protein-coupled receptors (GPCRs). There is increasing evidence that LPA signaling reprograms gene expression, but the GPCR-induced pathways connecting LPA receptor stimulation to downstream transcription factors are not well characterized. Here, we identify the adapter proteins Bcl10 and Malt1 as essential mediators of LPA-induced NF-kappa B activation. Both proteins were previously known to activate NF-kappa B in response to antigen receptor ligation on lymphocytes, but their functions in nonimmune cells are still largely undefined. By using murine embryonic fibroblasts from Bcl10- or Malt1-deficient mice as a genetic model, we report that Bcl10 and Malt1 are critically required for the degradation of I kappa B-alpha and the subsequent NF-kappa B induction in response to LPA stimulation. Bcl10 and Malt1 cooperate with PKCs selectively for LPA-induced NF-kappa B activation but are dispensable for the activation of the Jnk, p38, Erk MAP kinase, and Akt signaling pathways. In a biological readout, we demonstrate that LPA-induced IL-6 production is abolished in the absence of Bcl10. Thus, our results identify a NF-kappa B-inducing signaling pathway downstream of GPCRs and reveal previously unrecognized functions for Bcl10/Malt1 signaling in nonimmune cells.
机译：溶血磷脂酸（LPA）是一种有效的生物活性磷脂，可通过作用于相关的G蛋白偶联受体（GPCR）来刺激各种细胞反应。越来越多的证据表明，LPA信号转导可重编程基因表达，但GPCR诱导的将LPA受体刺激与下游转录因子连接的途径尚不清楚。在这里，我们确定衔接蛋白Bcl10和Malt1是LPA诱导的NF-κB激活的必要介体。先前已知这两种蛋白都可响应淋巴细胞上的抗原受体连接而激活NF-κB，但它们在非免疫细胞中的功能仍不清楚。通过使用来自Bcl10-或Malt1缺陷小鼠的鼠胚成纤维细胞作为遗传模型，我们报道Bcl10和Malt1是IκB-α降解以及随后的LPA刺激引起的NF-κB诱导的关键条件。 Bcl10和Malt1与PKC选择性合作，以LPA诱导的NF-κB活化，但对于Jnk，p38，Erk MAP激酶和Akt信号通路的活化是必不可少的。在生物学读数中，我们证明了在不存在Bcl10的情况下LPA诱导的IL-6产生被废除了。因此，我们的研究结果确定了GPCR下游的NF-κB诱导信号传导途径，并揭示了非免疫细胞中Bcl10 / Malt1信号传导先前无法识别的功能。

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