title: Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance.
abstract: Animal cells control their membrane lipid composition within narrow limits, but the sensing mechanisms underlying this control are largely unknown. Recent studies disclosed a protein network that controls the level of one lipid-cholesterol. This network resides in the endoplasmic reticulum (ER). A key component is Scap, a tetrameric ER membrane protein that binds cholesterol. Cholesterol binding prevents Scap from transporting SREBPs to the Golgi for activation. Using a new method to purify ER membranes from cultured cells, we show that Scap responds cooperatively to ER cholesterol levels. When ER cholesterol exceeds 5% of total ER lipids (molar basis), SREBP-2 transport is abruptly blocked. Transport resumes when ER cholesterol falls below the 5% threshold. The 5% threshold is lowered to 3% when cells overexpress Insig-1, a Scap-binding protein. Cooperative interactions between cholesterol, Scap, and Insig create a sensitive switch that controls the cholesterol composition of cell membranes with remarkable precision.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Radhakrishnan
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: Michael S
authors.initials: MS
authors.lastname: Brown
mesh_terms: D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D013058:Mass Spectrometry; D011499:Protein Processing, Post-Translational; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis / Q000378:metabolism*; D013997:Time Factors
chemical_list: C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol