Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP)

J Biol Chem. 2014 Mar 14;289(11):7547-57. doi: 10.1074/jbc.M113.545699. Epub 2014 Jan 29.

Abstract

Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipogenesis. Release of membrane-bound SREBP requires SREBP cleavage-activating protein (SCAP) to escort SREBP from the endoplasmic reticulum (ER) to the Golgi for cleavage by site-1 and site-2 proteases. SCAP then recycles to the ER for additional rounds of SREBP binding and transport. Mechanisms regulating ER-to-Golgi transport of SCAP-SREBP are understood in molecular detail, but little is known about SCAP recycling. Here, we have demonstrated that SCAP Golgi-to-ER transport requires cleavage of SREBP at site-1. Reductions in SREBP cleavage lead to SCAP degradation in lysosomes, providing additional negative feedback control to the SREBP pathway. Current models suggest that SREBP plays a passive role prior to cleavage. However, we show that SREBP actively prevents premature recycling of SCAP-SREBP until initiation of SREBP cleavage. SREBP regulates SCAP in human cells and yeast, indicating that this is an ancient regulatory mechanism.

Keywords: Cholesterol; Lipids; Lysosomes; Protein Degradation; Recycling; SCAP; SREBP; Transcription Factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cholesterol / metabolism
  • Cricetulus
  • Endoplasmic Reticulum / metabolism*
  • Genetic Vectors
  • Golgi Apparatus / metabolism*
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipids / chemistry*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Protein Binding
  • Schizosaccharomyces / metabolism
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Subcellular Fractions / metabolism
  • Transcription Factors / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Lipids
  • Membrane Proteins
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • Cholesterol