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
Cleavage of the membrane-bound transcription factor OASIS in response to endoplasmic reticulum stress.
Tomohiko Murakami,Shinichi Kondo,Maiko Ogata,Maiko Ogata,Soshi Kanemoto,Soshi Kanemoto,Atsushi Saito,Atsushi Saito,Akio Wanaka,Kazunori Imaizumi +9 more
TL;DR: It is shown that OASIS is processed by Site‐1 and ‐2 proteases (S1P and S2P), enzymes that reside at the Golgi apparatus and process activating transcription factor 6 (ATF6), in response to ER stress.
Book ChapterDOI
Sterol regulatory element-binding protein family as global regulators of lipid synthetic genes in energy metabolism.
TL;DR: DNA cis-elements that SREBPs bind, originally identified as sterol-regulatory elements (SREs), now expands to a variety of SRE-like sequences and some of E-boxes, which makes S REBPs eligible to regulate a wide range of lipid genes.
Journal ArticleDOI
Membrane Cholesterol: a Crucial Molecule Affecting Interactions of Microbial Pathogens with Mammalian Cells
P. Goluszko,Bogdan Nowicki +1 more
TL;DR: Several microorganisms and bacterial products target lipid rafts, membrane microdomains of eukaryotic cells enriched in cholesterol, which is a major sterol of mammalian cells.
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Cholesterol Accumulation Sequesters Rab9 and Disrupts Late Endosome Function in NPC1-deficient Cells
Ian G. Ganley,Suzanne R. Pfeffer +1 more
TL;DR: It is concluded that cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking.
Journal ArticleDOI
Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs
TL;DR: The results strongly suggest that the SREBP-1 transcription factors are the main mediators of insulin action on SRE BP-1c expression in human tissues.
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