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

• Published in: Nature communications Vol. 6; no. 1; p. 8100
• Main Authors: Xu, Daqian, Wang, Zheng, Zhang, Yuxue, Jiang, Wei, Pan, Yi, Song, Bao-Liang, Chen, Yan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.08.2015; Nature Pub. Group
• Subjects: Animals; Blotting, Western; CHO Cells; Cholesterol - metabolism; Cricetulus; Endoplasmic Reticulum - metabolism; Fluorescent Antibody Technique; Gene Knockdown Techniques; Golgi Apparatus - metabolism; HEK293 Cells; HeLa Cells; Hep G2 Cells; Hepatocytes - metabolism; Homeostasis; Humans; Immunoprecipitation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Liver - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Proteins - metabolism; Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9100

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.