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Erlins restrict SREBP activation in the ER and regulate cellular cholesterol homeostasis
Michael D Huber1, Paul W Vesely, Kaustuv Datta
1Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
The Journal of Cell Biology
|November 13, 2013
Summary
Erlins are novel cholesterol-binding proteins that regulate sterol regulatory element binding proteins (SREBPs). These proteins control cellular cholesterol by influencing the SREBP-Scap-Insig complex in the endoplasmic reticulum.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Cellular cholesterol homeostasis is crucial and regulated by endoplasmic reticulum (ER) sterol-sensing proteins.
- Sterol regulatory element binding proteins (SREBPs) are key transcription factors controlling cholesterol and fatty acid biosynthesis.
- Insig proteins, in conjunction with Scap, inhibit SREBP activation under cholesterol-sufficient conditions by retaining them in the ER.
Purpose of the Study:
- To identify novel regulators of the SREBP pathway.
- To investigate the role of erlin proteins in cellular cholesterol homeostasis.
- To elucidate the mechanism by which erlins interact with and modulate SREBP activity.
Main Methods:
- Depletion of erlin proteins in cultured cells.
- Analysis of SREBP activation and target gene expression.
- Co-immunoprecipitation assays to assess protein-protein interactions.
- Cholesterol binding assays and FRAP to study erlin-cholesterol interactions.
Main Results:
- Depletion of erlins in sterol-sufficient cells resulted in SREBP activation and increased expression of their target genes.
- Erlins were found to be physically associated with SREBPs, Scap, and Insig-1.
- Erlins exhibit specific and cooperative cholesterol binding, with their mobility in the ER altered by cholesterol levels, suggesting cholesterol-dependent regulation.
Conclusions:
- Erlins are novel cholesterol-binding proteins that directly regulate the SREBP machinery.
- Erlins likely stabilize the SREBP-Scap-Insig complex.
- Erlins may contribute to the highly cooperative control of cellular cholesterol levels.
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