Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK-NF-κB signaling mediated inflammation
Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK-NF-κB signaling mediated inflammation
复制标题
主要穹窿蛋白通过抑制 IKK-NF-kappa B 信号介导的炎症来抑制肥胖和动脉粥样硬化
DOI：
10.1038/s41467-019-09588-x
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发表时间：
2019-04-17
影响因子：
16.6
通讯作者：
Chen, Qi
中科院分区：
文献类型：
--
作者：
Ben, Jingjing;Jiang, Bin;Chen, Qi
巨噬细胞协调的低度慢性炎症在肥胖和动脉粥样硬化形成中起关键作用。然而，基本的调节机制仍然不完全清楚。在这里，我们确定主要穹窿蛋白（MVP），独特的细胞核糖核蛋白颗粒的主要成分，作为抑制因子NF-κ B信号在巨噬细胞。整体和骨髓特异性MVP基因敲除均能抑制高脂饮食诱导的小鼠肥胖、胰岛素抵抗、肝脂肪变性和动脉粥样硬化。MVP缺乏引起的代谢紊乱加剧伴随着微环境中巨噬细胞浸润增加和炎症反应增强。体外研究表明，MVP与TRAF 6相互作用，阻止其募集到IRAK 1和随后的寡聚化和泛素化。MVP及其α-螺旋结构域的过表达抑制TRAF 6的活性并抑制巨噬细胞炎症。我们的研究结果表明，巨噬细胞MVP构成了NF-κ B信号传导的关键约束，从而抑制代谢性疾病。
Macrophage-orchestrated, low-grade chronic inflammation plays a pivotal role in obesity and atherogenesis. However, the underlying regulatory mechanisms remain incompletely understood. Here, we identify major vault protein (MVP), the main component of unique cellular ribonucleoprotein particles, as a suppressor for NF-kappa B signaling in macrophages. Both global and myeloid-specific MVP gene knockout aggravates high-fat diet induced obesity, insulin resistance, hepatic steatosis and atherosclerosis in mice. The exacerbated metabolic disorders caused by MVP deficiency are accompanied with increased macrophage infiltration and heightened inflammatory responses in the microenvironments. In vitro studies reveal that MVP interacts with TRAF6 preventing its recruitment to IRAK1 and subsequent oligomerization and ubiquitination. Overexpression of MVP and its alpha-helical domain inhibits the activity of TRAF6 and suppresses macrophage inflammation. Our results demonstrate that macrophage MVP constitutes a key constraint of NF-kappa B signaling thereby suppressing metabolic diseases.