A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood

Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8. doi: 10.1073/pnas.96.20.11041.

Abstract

The integrity of cell membranes is maintained by a balance between the amount of cholesterol and the amounts of unsaturated and saturated fatty acids in phospholipids. This balance is maintained by membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that activate genes encoding enzymes of cholesterol and fatty acid biosynthesis. To enhance transcription, the active NH(2)-terminal domains of SREBPs are released from endoplasmic reticulum membranes by two sequential cleavages. The first is catalyzed by Site-1 protease (S1P), a membrane-bound subtilisin-related serine protease that cleaves the hydrophilic loop of SREBP that projects into the endoplasmic reticulum lumen. The second cleavage, at Site-2, requires the action of S2P, a hydrophobic protein that appears to be a zinc metalloprotease. This cleavage is unusual because it occurs within a membrane-spanning domain of SREBP. Sterols block SREBP processing by inhibiting S1P. This response is mediated by SREBP cleavage-activating protein (SCAP), a regulatory protein that activates S1P and also serves as a sterol sensor, losing its activity when sterols overaccumulate in cells. These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins*
  • Cholesterol / analysis*
  • Cholesterol / blood
  • DNA-Binding Proteins / physiology
  • Endopeptidases / genetics
  • Endopeptidases / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Lipids / analysis*
  • Membrane Proteins / physiology
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / physiology
  • Nuclear Proteins / physiology
  • Proprotein Convertases*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / physiology
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Lipids
  • Membrane Proteins
  • Nuclear Proteins
  • SREBF1 protein, human
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Cholesterol
  • Endopeptidases
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1
  • Metalloendopeptidases
  • MBTPS2 protein, human