title: A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood.
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.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. jgolds@mednet.swmed.edu
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
authors.forename: J L
authors.initials: JL
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002784:Cholesterol / Q000032:analysis* / Q000097:blood; D004268:DNA-Binding Proteins / Q000502:physiology; D010450:Endopeptidases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids / Q000032:analysis*; D008565:Membrane Proteins / Q000502:physiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D008565:Membrane Proteins; D009687:Nuclear Proteins; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol; D010450:Endopeptidases; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human