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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • INSIG1 protein, human
  • Insig1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RKTG protein, human
  • RKTG protein, mouse
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Proteins
  • Triglycerides
  • Cholesterol