The structurally and functionally complex endoplasmic reticulum (ER) hosts critical processes including lipid synthesis. Here, we focus on the functional characterization of transmembrane protein TMEM147, and report that it localizes at the ER and nuclear envelope in HeLa cells. Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the inner nuclear membrane and results in mistargeting of LBR to the ER. LBR possesses a modular structure and corresponding bifunctionality, acting in heterochromatin organization via its N-terminus and in cholesterol biosynthesis via its sterol-reductase C-terminal domain. We show that TMEM147 physically interacts with LBR, and that the C-terminus of LBR is essential for their functional interaction. We find that TMEM147 also physically interacts with the key sterol reductase DHCR7, which is involved in cholesterol biosynthesis. Similar to what was seen for LBR, TMEM147 downregulation results in a sharp decline of DHCR protein levels and co-ordinate transcriptional decreases of LBR and DHCR7 expression. Consistent with this, lipidomic analysis upon TMEM147 silencing identified changes in cellular cholesterol levels, cholesteryl ester levels and profile, and in cellular cholesterol uptake, raising the possibility that TMEM147 is an important new regulator of cholesterol homeostasis in cells.

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结构和功能复杂的内质网 (ER) 承载着包括脂质合成在内的关键过程。在这里，我们重点关注跨膜蛋白 TMEM147 的功能表征，并报告其定位于 HeLa 细胞的内质网和核膜。 TMEM147的沉默会大大降低内核膜上核纤层蛋白 B 受体 (LBR) 的水平，并导致 LBR 错误定位到 ER。 LBR 具有模块化结构和相应的双功能，通过其 N 端参与异染色质组织，并通过其甾醇还原酶 C 端结构域参与胆固醇生物合成。我们证明 TMEM147 与 LBR 发生物理相互作用，并且 LBR 的 C 末端对于它们的功能相互作用至关重要。我们发现 TMEM147 还与参与胆固醇生物合成的关键甾醇还原酶 DHCR7 发生物理相互作用。与 LBR 中观察到的情况类似， TMEM147下调导致 DHCR 蛋白水平急剧下降，并协调LBR和DHCR7表达的转录减少。与此一致的是， TMEM147沉默后的脂质组学分析发现了细胞胆固醇水平、胆固醇酯水平和概况以及细胞胆固醇摄取的变化，这提高了 TMEM147 是细胞中胆固醇稳态的重要新调节剂的可能性。

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