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PMID: 10500120 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 20 ·1999-09-28 ·Pages 11041-8

Brown MS, Goldstein JL

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.

MeSH Terms
Animals CCAAT-Enhancer-Binding Proteins Cholesterol/analysis,blood DNA-Binding Proteins/physiology Endopeptidases/genetics,physiology Humans Intracellular Signaling Peptides and Proteins Membrane Lipids/analysis Membrane Proteins/physiology Metalloendopeptidases/genetics,physiology Nuclear Proteins/physiology Proprotein Convertases Serine Endopeptidases/genetics,physiology Sterol Regulatory Element Binding Protein 1 Transcription Factors
Chemicals
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
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Brown M S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. [email protected]
Goldstein J L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.20.11041
Email
[email protected]
Published
1999-09-28
Pages
11041-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC34238
Subset
IM
Grants
NHLBI NIH HHS · P01 HL020948 · United States
NHLBI NIH HHS · HL20948 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.20.11041 PMC Full Text View journal details
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