Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig

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Abstract

Cholesterol synthesis in animals is controlled by the regulated transport of sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum to the Golgi, where the transcription factors are processed proteolytically to release active fragments. Transport is inhibited by either cholesterol or oxysterols, blocking cholesterol synthesis. Cholesterol acts by binding to the SREBP-escort protein Scap, thereby causing Scap to bind to anchor proteins called Insigs. Here, we show that oxysterols act by binding to Insigs, causing Insigs to bind to Scap. Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap. These studies define Insigs as oxysterol-binding proteins, explaining the long-known ability of oxysterols to inhibit cholesterol synthesis in animal cells.

Original languageEnglish (US)
Pages (from-to)6511-6518
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number16
DOIs
Publication statusPublished - Apr 17 2007

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Keywords

  • Cholesterol homeostasis
  • COPII vesicles
  • Scap
  • Sterol regulatory element-binding protein pathway

ASJC Scopus subject areas

  • Genetics
  • General

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