Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate Balance
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 k...
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| Veröffentlicht in: | Cell metabolism 2008-12, Vol.8 (6), p.512-521 |
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| creator | Radhakrishnan, Arun Goldstein, Joseph L. McDonald, Jeffrey G. Brown, Michael S. |
| description | 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. |
| doi_str_mv | 10.1016/j.cmet.2008.10.008 |
| format | Article |
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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. 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| ispartof | Cell metabolism, 2008-12, Vol.8 (6), p.512-521 |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Biological Transport CELLBIO Cells, Cultured CHO Cells Cholesterol - metabolism Cricetinae Cricetulus Endoplasmic Reticulum - metabolism Golgi Apparatus - metabolism HUMDISEASE Mass Spectrometry Protein Processing, Post-Translational Sterol Regulatory Element Binding Protein 2 - biosynthesis Sterol Regulatory Element Binding Protein 2 - metabolism Time Factors |
| title | Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate Balance |
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