The non-canonical NF-κB pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking
The non-canonical NF-κB pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking
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DOI：
10.1007/s11427-018-9339-0
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发表时间：
2018-08
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影响因子：
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通讯作者：
Yacheng Liao;Jian Wei;Ju-Qiong Wang;Xiongjie Shi;Jie Luo;B. Song
中科院分区：
文献类型：
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作者：
Yacheng Liao;Jian Wei;Ju-Qiong Wang;Xiongjie Shi;Jie Luo;B. Song
Niemann-Pick C2(NPC2)是一种溶酶体腔蛋白，与NPC1协同作用，介导低密度脂蛋白衍生的胆固醇从溶酶体中排出。核因子kappaB亚单位2(NF-κB2)蛋白是核因子-κB转录因子复合体的一个组成部分，与免疫和炎症反应密切相关。在此，我们报道了NF-κB2通过控制NPC2的表达来调节细胞内胆固醇的运输。RNAi介导的NF-κB2的破坏以及非规范的NF-κB途径的其他信号成员导致细胞内胆固醇积聚。阻断非规范的NF-κB途径可抑制NPC2的表达，而淋巴毒素β受体(LTβR)激活或BAFF受体(BAFR)刺激可上调NPC2mRNA的丰度和蛋白水平。此外，NF-κB2通过直接与其启动子区域结合来激活NPC2转录。我们还观察到了NF-κB2缺陷斑马鱼胚胎和NF-κB2突变小鼠体内胆固醇的积聚。总而言之，这些数据确定了非规范的NF-κB途径在细胞内胆固醇运输中的调节作用，并表明胆固醇运输和免疫系统之间的联系。
Niemann-Pick type C2 (NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of low-density lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2 (NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption ofNF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor (LTβR) activation or Baff receptor (BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activatedNPC2transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.