The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi contact sites
The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi contact sites
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ER 胆固醇传感器 SCAP 促进 ER-高尔基体接触位点的 CARTS 生物发生
DOI：
10.1101/679936
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Tagaya Mitsuo
中科院分区：
文献类型：
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作者：
Wakana Yuichi;Hayashi Kaito;Nemoto Takumi;Watanabe Chiaki;Taoka Masato;Campelo Felix;Kumata Hidetoshi;Umemura Tomonari;Inoue Hiroki;Arasaki Kohei;Tagaya Mitsuo
响应胆固醇剥夺，SCAP护送SREBP转录因子从内质网（ER）到高尔基复合体进行蛋白水解激活，导致胆固醇合成和摄取的基因表达。在这里，我们表明，在胆固醇喂养的细胞ER-本地化的SCAP相互作用，通过Sac 1磷酸肌醇4-磷酸（PI 4P）磷酸酶与VAP/OSBP复合物，介导ER胆固醇和高尔基体PI 4P在ER-高尔基体接触网站的逆转运。SCAP敲低可能由于胆固醇转运缺陷而抑制了PI 4P的周转，并改变了VAP/OSBP复合物的亚细胞分布。正如在ER-高尔基体接触位点的脂质转移复合物的扰动的情况下，SCAP敲低抑制了thetrans-高尔基体网络衍生的运输载体CARTS的生物合成，这是逆转野生型SCAP的表达，但不是胆固醇敏感缺陷突变体。总之，我们的研究结果揭示了一个新的作用，SCAP在胆固醇喂养条件下，在促进CARTS的生物合成在ER-高尔基体接触sites，取决于ER cholesterol.SummarySCAP是胆固醇代谢的关键调节蛋白。Wakana等人描述了SCAP在控制高尔基体PI 4P周转和高尔基体衍生的转运载体CARTS的生物发生中的新作用，所述转运载体CARTS经由ER-高尔基体接触位点处的胆固醇/PI 4P交换机制。
In response to cholesterol deprivation, SCAP escorts SREBP transcription factors from the endoplasmic reticulum (ER) to the Golgi complex for their proteolytic activation, leading to gene expression for cholesterol synthesis and uptake. Here we show that in cholesterol-fed cells ER-localized SCAP interacts through Sac1 phosphoinositide 4-phosphate (PI4P) phosphatase with a VAP/OSBP complex, which mediates counter-transport of ER cholesterol and Golgi PI4P at ER-Golgi contact sites. SCAP knockdown inhibited the turnover of PI4P perhaps due to a cholesterol transport defect and altered the subcellular distribution of the VAP/OSBP complex. As in the case of perturbation of lipid transfer complexes at ER-Golgi contact sites, SCAP knockdown inhibited the biogenesis of thetrans-Golgi network-derived transport carriers CARTS, which was reversed by expression of wild-type SCAP but not cholesterol sensing-defective mutants. Altogether, our findings reveal a new role of SCAP under cholesterol-fed conditions in the facilitation of CARTS biogenesis at ER-Golgi contact sites, depending on the ER cholesterol.SummarySCAP is the key regulatory protein in cholesterol metabolism. Wakana et al. describe a new role of SCAP in controlling Golgi PI4P turnover and the biogenesis of the Golgi-derived transport carries CARTS via cholesterol/PI4P exchange machinery at ER-Golgi contact sites.