Crucial Step in Cholesterol Homeostasis
Open accessAbstract
Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER. In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis. Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER. Overexpression of INSIG-1 increases the sensitivity of cells to sterol-mediated inhibition of SREBP processing. Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated inhibition of ER exit. By facilitating sterol-dependent ER retention of SCAP, INSIG-1 plays a central role in cholesterol homeostasis.
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- Authors
- Yang, T., Espenshade, P. J., Wright, M. E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J. L., & Brown, M. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Institute for Systems Biology (US)
- Corresponding author
- Goldstein, Joseph L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 110
- Issue
- 4
- Pages
- 489-500
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2097632838
- Cited by
- 987
- References
- 27
- Citations by year
- 2026: 26 · 2025: 27 · 2024: 43 · 2023: 39 · 2022: 48 · 2021: 46 · 2020: 36 · 2019: 37 · 2018: 37 · 2017: 41 · 2016: 40 · 2015: 38 · 2014: 49 · 2013: 31 · 2012: 49
- FWCI
- 44.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r33ca084698-04)
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Cancer Institute (1R33 CA84698)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- INSIG1, SCAP, SREBP, cholesterol homeostasis, sterol sensing, endoplasmic reticulum retention, cholesterol biosynthesis, ER-Golgi transport, protein-protein interaction, sterol depletion
- MeSH terms
- Cell Membrane, Cells, Cultured, Cholesterol, DNA-Binding Proteins, Endoplasmic Reticulum, Eukaryotic Cells, Gene Expression Regulation, Genetic Vectors, Golgi Apparatus, Homeostasis, Humans, Membrane Proteins, Mutation, Peptide Hydrolases, Protein Binding, Proteins, Sterols, Transcription Factors, Transfection, Protein Structure, Tertiary, Protein Transport, CCAAT-Enhancer-Binding Proteins, Intracellular Signaling Peptides and Proteins, Sterol Regulatory Element Binding Protein 1
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