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Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles

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Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles. / Dupont Juhl, Alice; Lund, Frederik W; Jensen, Maria Louise V. et al.
I: Chemistry and Physics of Lipids, Bind 235, 105047, 03.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Harvard

Dupont Juhl, A, Lund, FW, Jensen, MLV, Szomek, M, Würtz Heegaard, C, Guttmann, P, Werner, S, McNally, J, Schneider, G, Kapishnikov, S & Wüstner, D 2021, 'Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles', Chemistry and Physics of Lipids, bind 235, 105047. https://doi.org/10.1016/j.chemphyslip.2020.105047

APA

Dupont Juhl, A., Lund, F. W., Jensen, M. L. V., Szomek, M., Würtz Heegaard, C., Guttmann, P., Werner, S., McNally, J., Schneider, G., Kapishnikov, S., & Wüstner, D. (2021). Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles. Chemistry and Physics of Lipids, 235, [105047]. https://doi.org/10.1016/j.chemphyslip.2020.105047

CBE

Dupont Juhl A, Lund FW, Jensen MLV, Szomek M, Würtz Heegaard C, Guttmann P, Werner S, McNally J, Schneider G, Kapishnikov S, et al. 2021. Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles. Chemistry and Physics of Lipids. 235:Article 105047. https://doi.org/10.1016/j.chemphyslip.2020.105047

MLA

Dupont Juhl, Alice et al. "Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles". Chemistry and Physics of Lipids. 2021. 235. https://doi.org/10.1016/j.chemphyslip.2020.105047

Vancouver

Dupont Juhl A, Lund FW, Jensen MLV, Szomek M, Würtz Heegaard C, Guttmann P et al. Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles. Chemistry and Physics of Lipids. 2021 mar.;235:105047. doi: 10.1016/j.chemphyslip.2020.105047

Author

Dupont Juhl, Alice ; Lund, Frederik W ; Jensen, Maria Louise V. et al. / Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles. I: Chemistry and Physics of Lipids. 2021 ; Bind 235.

Bibtex

@article{7a992662d6a3453b80ce61a38542a38a,
title = "Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles",
abstract = "The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in the lumen of late endosomes and lysosomes (LE/LYSs). Absence of functional NPC2 leads to endo-lysosomal buildup of cholesterol and other lipids. How NPC2{\textquoteright}s known capacity to transport cholesterol between model membranes is linked to its function in living cells is not known. Using quantitative live-cell imaging combined with modeling of the efflux kinetics, we show that NPC2-deficient human fibroblasts can export the cholesterol analog dehydroergosterol (DHE) from LE/LYSs. Internalized NPC2 accelerated sterol efflux extensively, accompanied by reallocation of LE/LYSs containing fluorescent NPC2 and DHE to the cell periphery. Using quantitative fluorescence loss in photobleaching of TopFluor-cholesterol (TF-Chol), we estimate a residence time for a rapidly exchanging sterol pool in LE/LYSs localized in close proximity to the plasma membrane (PM), of less than one min and observed non-vesicular sterol exchange between LE/LYSs and the PM. Excess sterol was released from the PM by shedding of cholesterol-rich vesicles. The ultrastructure of such vesicles was analyzed by combined fluorescence and cryo soft X-ray tomography (SXT), revealing that they can contain lysosomal cargo and intraluminal vesicles. Treating cells with apoprotein A1 and with nuclear receptor liver X-receptor (LXR) agonists to upregulate expression of ABC transporters enhanced cholesterol efflux from the PM, at least partly by accelerating vesicle release. We conclude that NPC2 inside LE/LYSs facilitates non-vesicular sterol exchange with the PM for subsequent sterol efflux to acceptor proteins and for shedding of sterol-rich vesicles from the cell surface.",
keywords = "Cholesterol efflux, Extracellular vesicles, Fluorescence, Image analysis, Niemann-Pick type C disease, Soft X-ray tomography",
author = "{Dupont Juhl}, Alice and Lund, {Frederik W} and Jensen, {Maria Louise V.} and Maria Szomek and {W{\"u}rtz Heegaard}, Christian and Peter Guttmann and Stephan Werner and James McNally and Gerd Schneider and Sergey Kapishnikov and Daniel W{\"u}stner",
year = "2021",
month = mar,
doi = "10.1016/j.chemphyslip.2020.105047",
language = "English",
volume = "235",
journal = "Chemistry and Physics of Lipids",
issn = "0009-3084",
publisher = "Elsevier Ireland Ltd.",

}

RIS

TY - JOUR

T1 - Niemann Pick C2 protein enables cholesterol transfer from endo-lysosomes to the plasma membrane for efflux by shedding of extracellular vesicles

AU - Dupont Juhl, Alice

AU - Lund, Frederik W

AU - Jensen, Maria Louise V.

AU - Szomek, Maria

AU - Würtz Heegaard, Christian

AU - Guttmann, Peter

AU - Werner, Stephan

AU - McNally, James

AU - Schneider, Gerd

AU - Kapishnikov, Sergey

AU - Wüstner, Daniel

PY - 2021/3

Y1 - 2021/3

N2 - The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in the lumen of late endosomes and lysosomes (LE/LYSs). Absence of functional NPC2 leads to endo-lysosomal buildup of cholesterol and other lipids. How NPC2’s known capacity to transport cholesterol between model membranes is linked to its function in living cells is not known. Using quantitative live-cell imaging combined with modeling of the efflux kinetics, we show that NPC2-deficient human fibroblasts can export the cholesterol analog dehydroergosterol (DHE) from LE/LYSs. Internalized NPC2 accelerated sterol efflux extensively, accompanied by reallocation of LE/LYSs containing fluorescent NPC2 and DHE to the cell periphery. Using quantitative fluorescence loss in photobleaching of TopFluor-cholesterol (TF-Chol), we estimate a residence time for a rapidly exchanging sterol pool in LE/LYSs localized in close proximity to the plasma membrane (PM), of less than one min and observed non-vesicular sterol exchange between LE/LYSs and the PM. Excess sterol was released from the PM by shedding of cholesterol-rich vesicles. The ultrastructure of such vesicles was analyzed by combined fluorescence and cryo soft X-ray tomography (SXT), revealing that they can contain lysosomal cargo and intraluminal vesicles. Treating cells with apoprotein A1 and with nuclear receptor liver X-receptor (LXR) agonists to upregulate expression of ABC transporters enhanced cholesterol efflux from the PM, at least partly by accelerating vesicle release. We conclude that NPC2 inside LE/LYSs facilitates non-vesicular sterol exchange with the PM for subsequent sterol efflux to acceptor proteins and for shedding of sterol-rich vesicles from the cell surface.

AB - The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in the lumen of late endosomes and lysosomes (LE/LYSs). Absence of functional NPC2 leads to endo-lysosomal buildup of cholesterol and other lipids. How NPC2’s known capacity to transport cholesterol between model membranes is linked to its function in living cells is not known. Using quantitative live-cell imaging combined with modeling of the efflux kinetics, we show that NPC2-deficient human fibroblasts can export the cholesterol analog dehydroergosterol (DHE) from LE/LYSs. Internalized NPC2 accelerated sterol efflux extensively, accompanied by reallocation of LE/LYSs containing fluorescent NPC2 and DHE to the cell periphery. Using quantitative fluorescence loss in photobleaching of TopFluor-cholesterol (TF-Chol), we estimate a residence time for a rapidly exchanging sterol pool in LE/LYSs localized in close proximity to the plasma membrane (PM), of less than one min and observed non-vesicular sterol exchange between LE/LYSs and the PM. Excess sterol was released from the PM by shedding of cholesterol-rich vesicles. The ultrastructure of such vesicles was analyzed by combined fluorescence and cryo soft X-ray tomography (SXT), revealing that they can contain lysosomal cargo and intraluminal vesicles. Treating cells with apoprotein A1 and with nuclear receptor liver X-receptor (LXR) agonists to upregulate expression of ABC transporters enhanced cholesterol efflux from the PM, at least partly by accelerating vesicle release. We conclude that NPC2 inside LE/LYSs facilitates non-vesicular sterol exchange with the PM for subsequent sterol efflux to acceptor proteins and for shedding of sterol-rich vesicles from the cell surface.

KW - Cholesterol efflux

KW - Extracellular vesicles

KW - Fluorescence

KW - Image analysis

KW - Niemann-Pick type C disease

KW - Soft X-ray tomography

UR - http://www.scopus.com/inward/record.url?scp=85101301186&partnerID=8YFLogxK

U2 - 10.1016/j.chemphyslip.2020.105047

DO - 10.1016/j.chemphyslip.2020.105047

M3 - Journal article

C2 - 33422548

VL - 235

JO - Chemistry and Physics of Lipids

JF - Chemistry and Physics of Lipids

SN - 0009-3084

M1 - 105047

ER -