A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
TLDR
These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.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 NH2-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.read more
Citations
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Journal ArticleDOI
Intracellular biosynthesis of lipids and cholesterol by Scap and Insig in mesenchymal cells regulates long bone growth and chondrocyte homeostasis.
Hidetoshi Tsushima,Yuning J. Tang,Vijitha Puviindran,Shu Hsuan Claire Hsu,Puviindran Nadesan,Chunying Yu,Hongyuan Zhang,Anthony J. Mirando,Matthew J. Hilton,Benjamin A. Alman +9 more
TL;DR: Precise regulation of intracellular biosynthesis is required for chondrocyte homeostasis and long bone growth, and pharmacological modulation of cholesterol biosynthesis as a therapy for select cartilage pathologies is supported.
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HDL activates expression of genes stimulating cholesterol efflux in human monocyte-derived macrophages.
Alexander N. Orekhov,Tatiana Pushkarsky,Yumiko Oishi,Nikita G. Nikiforov,Andrey V. Zhelankin,Larisa Dubrovsky,Vsevolod J. Makeev,Kathy K Foxx,Xueting Jin,Howard S. Kruth,Igor A. Sobenin,Vasily N. Sukhorukov,Emile Zakiev,Anatol Kontush,Wilfried Le Goff,Michael Bukrinsky +15 more
TL;DR: Results indicate that HDL particles stimulate expression of genes that enhance cellular cholesterol transfer to HDL, which is a key event in pathogenesis of atherosclerosis.
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Sterol Regulatory Element Binding Protein (SREBP)-1 is a novel regulator of the Transforming Growth Factor (TGF)-β receptor I (TβRI) through exosomal secretion.
Richard Van Krieken,Guang Chen,Bo Gao,Jolene Read,Hassan A. Al Saleh,Renzhong Li,Khalid Al-Nedawi,Joan C. Krepinsky +7 more
TL;DR: A novel role for SREBP-1 is identified as a cell surface retention factor for TβRI in mesangial cells, preventing its secretion in exosomes, which may provide a novel therapeutic strategy for diabetic nephropathy which targets multiple aspects of TGFβ signaling and matrix upregulation.
Book ChapterDOI
Regulated Intramembrane Proteolysis
TL;DR: Regulated intramembrane proteolysis is a mechanism for signal transduction that involves the generation of regulatory molecules from membrane proteins through proteolytic cleavage that influences processes as diverse as cellular differentiation, lipid metabolism, immune defense, and the response to unfolded proteins.
Journal ArticleDOI
Analysis of SCAP N-glycosylation and Trafficking in Human Cells
TL;DR: A protocol for the isolation of membrane fractions in human cells and the preparation of the samples for the detection of SCAP N-glycosylation and total protein by using western blot is described and a method to monitor SCAP trafficking by using confocal microscopy is provided.
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