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 of NF-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 activated NPC2 transcription 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.

中文翻译：

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非规范的NF-κB途径促进NPC2表达并调节细胞内胆固醇的运输。

Niemann-Pick C2型（NPC2）是一种溶酶体腔蛋白，与NPC1协同起作用，可介导低密度脂蛋白衍生的胆固醇从溶酶体中流出。核因子κB亚基2（NF-κB2）蛋白是NF-κB转录因子复合物的一个组成部分，与免疫和炎症反应密切相关。在这里，我们报道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以及非经典NF-κB途径的其他信号传导成员的破坏，引起细胞内胆固醇的积累。非典型的NF-κB通路的阻滞抑制了NPC2的表达，而淋巴毒素β受体（LTβR）激活或Baff受体（BaffR）刺激则上调了NPC2的mRNA丰度和蛋白质水平。进一步，NF-κB2通过直接与其启动子区域结合来激活NPC2转录。我们还观察到缺乏NF-κB2的斑马鱼胚胎和NF-κB2突变小鼠中的胆固醇积累。总的来说，这些数据确定了非经典的NF-κB通路在细胞内胆固醇运输中的调节作用，并暗示了胆固醇运输与免疫系统之间的联系。