Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts

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Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts. / Berzina, Zane; Solanko, Lukasz M.; Mehadi, Ahmed S.; Jensen, Maria Louise V.; Lund, Frederik W.; Modzel, Maciej; Szomek, Maria; Solanko, Katarzyna A.; Dupont, Alice; Nielsen, Gitte Krogh; Heegaard, Christian W.; Ejsing, Christer S.; Wüstner, Daniel.

In: Chemistry and Physics of Lipids, Vol. 213, 01.07.2018, p. 48-61.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Berzina, Z, Solanko, LM, Mehadi, AS, Jensen, MLV, Lund, FW, Modzel, M, Szomek, M, Solanko, KA, Dupont, A, Nielsen, GK, Heegaard, CW, Ejsing, CS & Wüstner, D 2018, 'Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts', Chemistry and Physics of Lipids, vol. 213, pp. 48-61. https://doi.org/10.1016/j.chemphyslip.2018.03.006

APA

Berzina, Z., Solanko, L. M., Mehadi, A. S., Jensen, M. L. V., Lund, F. W., Modzel, M., ... Wüstner, D. (2018). Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts. Chemistry and Physics of Lipids, 213, 48-61. https://doi.org/10.1016/j.chemphyslip.2018.03.006

CBE

Berzina Z, Solanko LM, Mehadi AS, Jensen MLV, Lund FW, Modzel M, Szomek M, Solanko KA, Dupont A, Nielsen GK, Heegaard CW, Ejsing CS, Wüstner D. 2018. Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts. Chemistry and Physics of Lipids. 213:48-61. https://doi.org/10.1016/j.chemphyslip.2018.03.006

MLA

Vancouver

Berzina Z, Solanko LM, Mehadi AS, Jensen MLV, Lund FW, Modzel M et al. Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts. Chemistry and Physics of Lipids. 2018 Jul 1;213:48-61. https://doi.org/10.1016/j.chemphyslip.2018.03.006

Author

Berzina, Zane ; Solanko, Lukasz M. ; Mehadi, Ahmed S. ; Jensen, Maria Louise V. ; Lund, Frederik W. ; Modzel, Maciej ; Szomek, Maria ; Solanko, Katarzyna A. ; Dupont, Alice ; Nielsen, Gitte Krogh ; Heegaard, Christian W. ; Ejsing, Christer S. ; Wüstner, Daniel. / Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts. In: Chemistry and Physics of Lipids. 2018 ; Vol. 213. pp. 48-61.

Bibtex

@article{2a87226d8fe6488e9856ad5134ce6e03,
title = "Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts",
abstract = "Niemann-Pick disease type C2 is a lipid storage disorder in which mutations in the NPC2 protein cause accumulation of lipoprotein-derived cholesterol in late endosomes and lysosomes (LE/LYSs). Whether cholesterol delivered by other means to NPC2 deficient cells also accumulates in LE/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous diffusion in disease cells (D ∼ 4.6∙10−4 μm2/sec; α∼0.76), a small pool of sterol could exchange rapidly with D ∼ 3 μm2/s between LE/LYSs, as shown by fluorescence recovery after photobleaching (FRAP). By quantitative lipid mass spectrometry we found that esterification of 13C-labeled cholesterol but not of DHE is reduced 10-fold in disease fibroblasts compared to control cells. Internalized NPC2 rescued the sterol storage phenotype and strongly expanded the dynamic sterol pool seen in FRAP experiments. Together, our study shows that cholesterol esterification and trafficking of sterols between the PM and LE/LYSs depends on a functional NPC2 protein. NPC2 likely acts inside LE/LYSs from where it increases non-vesicular sterol exchange with other organelles.",
keywords = "Cholesterol, Diffusion, Fluorescence recovery after photobleaching, Kinetics, Lipid mass spectrometry, Lysosome, Niemann-Pick disease type C2, Non-vesicular, Vesicle tracking",
author = "Zane Berzina and Solanko, {Lukasz M.} and Mehadi, {Ahmed S.} and Jensen, {Maria Louise V.} and Lund, {Frederik W.} and Maciej Modzel and Maria Szomek and Solanko, {Katarzyna A.} and Alice Dupont and Nielsen, {Gitte Krogh} and Heegaard, {Christian W.} and Ejsing, {Christer S.} and Daniel W{\"u}stner",
year = "2018",
month = "7",
day = "1",
doi = "10.1016/j.chemphyslip.2018.03.006",
language = "English",
volume = "213",
pages = "48--61",
journal = "Chemistry and Physics of Lipids",
issn = "0009-3084",
publisher = "Elsevier Ireland Ltd.",

}

RIS

TY - JOUR

T1 - Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts

AU - Berzina, Zane

AU - Solanko, Lukasz M.

AU - Mehadi, Ahmed S.

AU - Jensen, Maria Louise V.

AU - Lund, Frederik W.

AU - Modzel, Maciej

AU - Szomek, Maria

AU - Solanko, Katarzyna A.

AU - Dupont, Alice

AU - Nielsen, Gitte Krogh

AU - Heegaard, Christian W.

AU - Ejsing, Christer S.

AU - Wüstner, Daniel

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Niemann-Pick disease type C2 is a lipid storage disorder in which mutations in the NPC2 protein cause accumulation of lipoprotein-derived cholesterol in late endosomes and lysosomes (LE/LYSs). Whether cholesterol delivered by other means to NPC2 deficient cells also accumulates in LE/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous diffusion in disease cells (D ∼ 4.6∙10−4 μm2/sec; α∼0.76), a small pool of sterol could exchange rapidly with D ∼ 3 μm2/s between LE/LYSs, as shown by fluorescence recovery after photobleaching (FRAP). By quantitative lipid mass spectrometry we found that esterification of 13C-labeled cholesterol but not of DHE is reduced 10-fold in disease fibroblasts compared to control cells. Internalized NPC2 rescued the sterol storage phenotype and strongly expanded the dynamic sterol pool seen in FRAP experiments. Together, our study shows that cholesterol esterification and trafficking of sterols between the PM and LE/LYSs depends on a functional NPC2 protein. NPC2 likely acts inside LE/LYSs from where it increases non-vesicular sterol exchange with other organelles.

AB - Niemann-Pick disease type C2 is a lipid storage disorder in which mutations in the NPC2 protein cause accumulation of lipoprotein-derived cholesterol in late endosomes and lysosomes (LE/LYSs). Whether cholesterol delivered by other means to NPC2 deficient cells also accumulates in LE/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous diffusion in disease cells (D ∼ 4.6∙10−4 μm2/sec; α∼0.76), a small pool of sterol could exchange rapidly with D ∼ 3 μm2/s between LE/LYSs, as shown by fluorescence recovery after photobleaching (FRAP). By quantitative lipid mass spectrometry we found that esterification of 13C-labeled cholesterol but not of DHE is reduced 10-fold in disease fibroblasts compared to control cells. Internalized NPC2 rescued the sterol storage phenotype and strongly expanded the dynamic sterol pool seen in FRAP experiments. Together, our study shows that cholesterol esterification and trafficking of sterols between the PM and LE/LYSs depends on a functional NPC2 protein. NPC2 likely acts inside LE/LYSs from where it increases non-vesicular sterol exchange with other organelles.

KW - Cholesterol

KW - Diffusion

KW - Fluorescence recovery after photobleaching

KW - Kinetics

KW - Lipid mass spectrometry

KW - Lysosome

KW - Niemann-Pick disease type C2

KW - Non-vesicular

KW - Vesicle tracking

UR - http://www.scopus.com/inward/record.url?scp=85044610012&partnerID=8YFLogxK

U2 - 10.1016/j.chemphyslip.2018.03.006

DO - 10.1016/j.chemphyslip.2018.03.006

M3 - Journal article

C2 - 29580834

AN - SCOPUS:85044610012

VL - 213

SP - 48

EP - 61

JO - Chemistry and Physics of Lipids

JF - Chemistry and Physics of Lipids

SN - 0009-3084

ER -