CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells
CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells
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DOI：
10.1073/pnas.0601947103
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发表时间：
2007-01-02
影响因子：
11.1
通讯作者：
Lucas, Peter C.
中科院分区：
文献类型：
--
作者：
McAllister-Lucas, Linda M.;Ruland, Juergen;Lucas, Peter C.
血管紧张素II（Ang II）是一种肽激素，与许多细胞因子一样，作为促炎剂和生长因子。在肝脏损伤后，该激素通过刺激肝细胞和肝星状细胞合成细胞外基质蛋白并分泌次级细胞因子以及通过刺激肌成纤维细胞增殖来辅助组织修复。然而，在慢性肝损伤的条件下，所有这些作用共同促进病理性肝纤维化。Ang III的这种作用大部分是由于促炎性NF-κ B转录因子响应于1型Ang II受体（一种G蛋白偶联受体）的刺激而激活。在这里，我们描述了一个以前未描述的信号通路介导的血管紧张素II依赖性激活NF-κ B B，这是由三个主要蛋白质，CARMA 3，Bcl 10和MALT 1。通过使用显性阴性突变体、RNAi或基因靶向阻断这些蛋白质中的任何一种的功能，可以有效地消除肝细胞中的Ang II依赖性NF-κ B活化。此外，Bcl 10（-/-）小鼠在Ang II治疗后显示出肝细胞因子产生缺陷。也有证据表明，该途径通过IKK γ（I κ B激酶复合物的调节亚基）的泛素化激活NF-κ B。这些结果阐明了一系列具体的分子事件，将1型Ang II受体的配体激活与NF-κ B转录因子的刺激联系起来。这些发现还揭示了CARMA，Bcl 10和MALT 1蛋白在免疫系统外细胞中的功能。
Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang III results from activation of the proinflammatory NF-kappa B transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-kappa B, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-kappa B activation in hepatocytes. In addition, Bcl10(-/-) mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-kappa B through ubiquitination of IKK gamma, the regulatory subunit of the I kappa B kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-kappa B transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.