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
Proteolytic Control of Lipid Metabolism.
TL;DR: The scope of this review will cover proteolytic events governing cellular lipid dynamics, starting with the classic example of sterol regulatory element-binding proteins (SREBPs), and then shifting to the mitochondrion, where a range of proteolytics events are critical for normal mitochondrial phospholipid metabolism and enforcing quality control therein.
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Smooth Muscle Cell—Macrophage Interactions Leading to Foam Cell Formation in Atherosclerosis: Location, Location, Location
TL;DR: An understanding of these SMC-macrophage interactions in foam cell formation and regression is expected to provide new therapeutic targets to reduce the burden of atherosclerosis for the prevention of coronary heart disease, stroke and peripheral vascular disease.
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Role of mitogen-activated protein kinases and protein kinase C in regulating low-density lipoprotein receptor expression.
TL;DR: The emerging picture from the above studies is that regulation of LDL receptor transcription results from the activity of a number of interlinked regulatory molecules and pathways, rather than from a single linear series of events.
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Genetic ablation of S6-kinase does not prevent processing of SREBP1.
TL;DR: Results suggest that S6-kinases 1 and 2 are dispensable for the induction of SREBP processing in the experimental systems used here and investigate whether ablation of different signalling molecules downstream of mTORC1 affects expression of S REBP targets genes.
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Review: dynamic stability of the interphase nucleus in health and disease.
TL;DR: Ongoing export of newly synthesized RNAs, as well as control of transcriptional activity, involves dynamic nucleocytoplasmic transport of proteins, which provides numerous opportunities for precise communication between spatially distant sites in the cell.
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TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
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