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PAQR3通过将Scap/SREBP复合物锚定到高尔基体来调节胆固醇稳态。

PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus.

作者信息

Xu Daqian, Wang Zheng, Zhang Yuxue, Jiang Wei, Pan Yi, Song Bao-Liang, Chen Yan

机构信息

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 20031, China.

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

出版信息

Nat Commun. 2015 Aug 27;6:8100. doi: 10.1038/ncomms9100.

DOI:10.1038/ncomms9100
PMID:26311497
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4560833/
Abstract

Cholesterol biosynthesis is regulated by transcription factors SREBPs and their escort protein Scap. On sterol depletion, Scap/SREBP complex is transported from endoplasmic reticulum (ER) to the Golgi apparatus where SREBP is activated. Under cholesterol sufficient condition, Insigs act as anchor proteins to retain Scap/SREBP in the ER. However, the anchor protein of Scap/SREBP in the Golgi is unknown. Here we report that a Golgi-localized membrane protein progestin and adipoQ receptors 3 (PAQR3) interacts with Scap and SREBP and tethers them to the Golgi. PAQR3 promotes Scap/SREBP complex formation, potentiates SREBP processing and enhances lipid synthesis. The mutually exclusive interaction between Scap and PAQR3 or Insig-1 is regulated by cholesterol level. PAQR3 knockdown in liver blunts SREBP pathway and decreases hepatic cholesterol content. Disrupting the interaction of PAQR3 with Scap/SREBP by a synthetic peptide inhibits SREBP processing and activation. Thus, PAQR3 regulates cholesterol homeostasis by anchoring Scap/SREBP to the Golgi and disruption of such function reduces cholesterol biosynthesis.

摘要

胆固醇生物合成受转录因子固醇调节元件结合蛋白（SREBPs）及其护送蛋白Scap调控。在固醇缺乏时，Scap/SREBP复合物从内质网（ER）转运至高尔基体，在高尔基体中SREBP被激活。在胆固醇充足的条件下，Insigs作为锚定蛋白将Scap/SREBP保留在内质网中。然而，Scap/SREBP在高尔基体中的锚定蛋白尚不清楚。在此我们报告，一种定位于高尔基体的膜蛋白孕激素和脂联素受体3（PAQR3）与Scap和SREBP相互作用，并将它们拴系在高尔基体上。PAQR3促进Scap/SREBP复合物的形成，增强SREBP的加工过程并促进脂质合成。Scap与PAQR3或Insig-1之间相互排斥的相互作用受胆固醇水平调节。肝脏中PAQR3的敲低会减弱SREBP途径并降低肝脏胆固醇含量。用合成肽破坏PAQR3与Scap/SREBP的相互作用会抑制SREBP的加工和激活。因此，PAQR3通过将Scap/SREBP锚定在高尔基体上来调节胆固醇稳态，破坏这种功能会减少胆固醇生物合成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/fef229894aa4/ncomms9100-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/70e4e7b58861/ncomms9100-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/d4dd75b05cf4/ncomms9100-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/a41faef3dd23/ncomms9100-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/53c53d1dc053/ncomms9100-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/981290c730ff/ncomms9100-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/fef229894aa4/ncomms9100-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/70e4e7b58861/ncomms9100-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/939cd8011c8b/ncomms9100-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/d4dd75b05cf4/ncomms9100-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/a41faef3dd23/ncomms9100-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/53c53d1dc053/ncomms9100-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/981290c730ff/ncomms9100-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9030/4560833/fef229894aa4/ncomms9100-f7.jpg

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