Sterol carrier protein-2: New roles in regulating lipid rafts and signaling

Schroeder, Friedhelm; Atshaves, Barbara P.; McIntosh, Avery L.; Gallegos, Adalberto M.; Storey, Stephen M.; Parr, Rebecca D.; Jefferson, John R.; Ball, Joseph A.; Kier, Ann B.

doi:10.1016/j.bbalip.2007.04.005

Cited by 75 publications

(72 citation statements)

References 230 publications

(305 reference statements)

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“…12,13 Genes involved in lipid transport were also upregulated, possibly in response to the accumulated glucocerebrosides; PLSCR3, encoding phospholipid scramblase 3, is involved in the trans-bilayer migration of membrane phospholipids, 52 and SCP2, encoding sterol carrier protein 2, is a nonspecific lipid transfer protein with a broad ligand spectrum (including sphingolipids) thought to be involved in regulating lipid signaling pathways in lipid raft/caveolae. 53 Another possibility is that these changes are not specific to GBA inhibition but could be caused by CBE directly affecting unrelated proteins and pathways. Further study of differentially regulated genes in other Gaucher models (such as shRNAtreated cells, cells from patients or from transgenic mice) and cell types (such as osteoblasts, osteoclasts, macrophages, or cell cocultures) will be necessary to further expand the pathophysiologic understanding of Gaucher disease.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

Campeau

Rafei²,

Boivin³

et al. 2009

Blood

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Section: Discussionmentioning

confidence: 99%

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

Campeau

Rafei²,

Boivin³

et al. 2009

Blood

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“…SCP-2 binds and enhances transfer not only of cholesterol, but also PI and sphingolipids (35,39,94,95). SCP-2 overexpression redistributes PI from intracellular sites to plasma membrane caveolae/lipid rafts (4,51,96,97), redistributes select sphingolipid signaling lipids to caveolae/lipid rafts (97,98), stimulates insulin mediated inositoltriphosphate production (94), and enhances conversion of ceramide to galactosyl-ceramide (95). By binding and transferring both signaling lipids such as PI, polyphosphoinositides and sphingolipids, SCP-2 interaction with caveolin-1 at PM caveolae may regulate signaling within the cell (rev.…”

Section: Discussionmentioning

confidence: 99%

“…By binding and transferring both signaling lipids such as PI, polyphosphoinositides and sphingolipids, SCP-2 interaction with caveolin-1 at PM caveolae may regulate signaling within the cell (rev. in (95,97).…”

Section: Discussionmentioning

confidence: 99%

A New N-Terminal Recognition Domain in Caveolin-1 Interacts with Sterol Carrier Protein-2 (SCP-2)

et al. 2007

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Although plasma membrane domains such as caveolae provide an organizing principle for signaling pathways and cholesterol homeostasis in the cell, relatively little is known regarding specific mechanisms whereby intracellular lipid binding proteins are targeted to caveolae. Therefore, the interaction between caveolin-1 and sterol carrier protein-2 (SCP-2), a protein that binds and transfers both cholesterol and signaling lipids (e.g. phosphatidylinositides, sphingolipids), was examined by yeast two-hybrid, in vitro binding, and fluorescence resonance energy transfer analyses (FRET). Results of the in vivo and in vitro assays identified for the first time the N-terminal aa1-32 amphipathic α-helix of SCP-2 functionally interacted with caveolin-1. This interaction was independent of the classic caveolin-1 scaffolding domain in which many signaling proteins interact. Instead, SCP-2 bound caveolin-1 through a new domain identified in the N-terminal domain of caveolin-1 between amino acids 32-55. Modeling studies suggested that electrostatic interactions between the SCP-2 N-terminal aa1-32 amphipathic α-helical domain (cationic, positively charged face) and the caveolin-1 N-terminal aa33-59 α-helix (anionic, negatively charged face) may significantly contribute to this interaction. These findings provide new insights on how SCP-2 enhances cholesterol retention within the cell as well as regulates the distribution of signaling lipids such as phosphoinositides and sphingolipids at plasma membrane caveolae.Keywords sterol carrier protein-2; caveolae; caveolin-1; caveolae; cholesterol; signaling Increasing evidence indicates that cholesterol found at the cell surface plasma membrane (PM) is not randomly distributed, but instead organized into both transbilayer (1,2) and lateral (3,4) cholesterol-rich (and/or sphingolipid-rich) domains that adopt a unique, liquidordered structural organization (4-7). It has been postulated that this self-assembling property of cholesterol (and also sphingolipids) into domains in turn forms the structural basis for selective membrane protein organization (8). Support for this hypothesis is from numerous studies demonstrating that many PM proteins are functionally organized into lipid rafts and/or caveolae, a sub-fraction of lipid rafts that have proven to be a remarkably stable † Acknowledgments: This work was supported in part by the USPHS National Institutes of Health GM31651 (FS and AK) and GM62326 (JMB).

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“…Concomitantly SCP-2 overexpression decreased the slower, vesicular cholesterol transfer -likely by binding and sequestering ligands (i.e. phosphatidylinositides, fatty acyl CoAs) that regulate vesicular trafficking (43,(47)(48)(49)(50)(51)(52)(53).…”

Section: Advent Of Fluorescent Sterolsmentioning

confidence: 99%

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

McIntosh

Atshaves

Huang

et al. 2008

Lipids

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Cholesterol itself has very few structural/chemical features suitable for real-time imaging in living cells. Thus, the advent of dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol, DHE] the fluorescent sterol most structurally and functionally similar to cholesterol to date, has proven to be a major asset for real-time probing/elucidating the sterol environment and intracellular sterol trafficking in living organisms. DHE is a naturally-occurring, fluorescent sterol analog that faithfully mimics many of the properties of cholesterol. Because these properties are very sensitive to sterol structure and degradation, such studies require the use of extremely pure (>98%) quantities of fluorescent sterol. DHE is readily bound by cholesterol-binding proteins, is incorporated into lipoproteins (from the diet of animals or by exchange in vitro), and for real-time imaging studies is easily incorporated into cultured cells where it co-distributes with endogenous sterol. Incorporation from an ethanolic stock solution to cell culture media is effective, but this process forms an aqueous dispersion of dehydroergosterol crystals which can result in endocytic cellular uptake and distribution into lysosomes which is problematic in imaging DHE at the plasma membrane of living cells. In contrast, monomeric DHE can be incorporated from unilamellar vesicles by exchange/fusion with the plasma membrane or from DHE-methyl-β-cyclodextrin (DHE-MβCD) complexes by exchange with the plasma membrane. Both of the latter techniques can deliver large quantities of monomeric dehydroergosterol with significant distribution into the plasma membrane. The properties and behavior of DHE in protein-binding, lipoproteins, model membranes, biological membranes, lipid rafts/caveolae, and real-time imaging in living cells indicate that this naturally-occurring fluorescent sterol is a useful mimic for probing the properties of cholesterol in these systems. Keywordsdehydroergosterol; cholesterol; ergosterol; fluorescent sterols; microscopy Historical PerspectiveIn order to resolve the dynamics and factors governing cholesterol trafficking within cells, it is important to recognize that the cholesterol molecule has very few polar constituents (Fig. 1A). Consequently, cholesterol is poorly soluble in aqueous environments such as cytosol as evidenced by critical micellar concentrations of cholesterol and other sterols being very low, *To whom correspondence should be addressed: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 862-1433, FAX: (979) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript near 20-30 nM (1-5). The physiological impact of cholesterol's low aqueous solubility is that spontaneous cholesterol desorption from the cytofacial leaflet of the plasma membrane or lysosomal membrane into the cytosol for transfer to intracellular sites for esterification, oxidation, or secretion is extremely slow (t 1/2 3 hours-days) (6-9). Therefore, it is important to resolve factors...

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Sterol carrier protein-2: New roles in regulating lipid rafts and signaling

Cited by 75 publications

References 230 publications

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

A New N-Terminal Recognition Domain in Caveolin-1 Interacts with Sterol Carrier Protein-2 (SCP-2)

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

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