Role for LAMP-2 in endosomal cholesterol transport.
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Role for LAMP-2 in endosomal cholesterol transport. / Schneede, Alexander; Schmidt, Christine K; Hölttä-Vuori, Maarit; Heeren, Jörg; Willenborg, Marion; Blanz, Judith; Domanskyy, Mykola; Breiden, Bernadette; Brodesser, Susanne; Landgrebe, Jobst; Sandhoff, Konrad; Ikonen, Elina; Saftig, Paul; Eskelinen, Eeva-Liisa.
In: J CELL MOL MED, Vol. 15, No. 2, 2, 2011, p. 280-295.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Role for LAMP-2 in endosomal cholesterol transport.
AU - Schneede, Alexander
AU - Schmidt, Christine K
AU - Hölttä-Vuori, Maarit
AU - Heeren, Jörg
AU - Willenborg, Marion
AU - Blanz, Judith
AU - Domanskyy, Mykola
AU - Breiden, Bernadette
AU - Brodesser, Susanne
AU - Landgrebe, Jobst
AU - Sandhoff, Konrad
AU - Ikonen, Elina
AU - Saftig, Paul
AU - Eskelinen, Eeva-Liisa
PY - 2011
Y1 - 2011
N2 - The mechanisms of endosomal and lysosomal cholesterol traffic are still poorly understood. We showed previously that unesterified cholesterol accumulates in the late endosomes and lysosomes of fibroblasts deficient in both lysosome associated membrane protein-2 (LAMP-2) and LAMP-1, two abundant membrane proteins of late endosomes and lysosomes. In this study we show that in cells deficient in both LAMP-1 and LAMP-2 (LAMP(-/-)), low-density lipoprotein (LDL) receptor levels and LDL uptake are increased as compared to wild-type cells. However, there is a defect in esterification of both endogenous and LDL cholesterol. These results suggest that LAMP(-/-) cells have a defect in cholesterol transport to the site of esterification in the endoplasmic reticulum, likely due to defective export of cholesterol out of late endosomes or lysosomes. We also show that cholesterol accumulates in LAMP-2 deficient liver and that overexpression of LAMP-2 retards the lysosomal cholesterol accumulation induced by U18666A. These results point to a critical role for LAMP-2 in endosomal/lysosomal cholesterol export. Moreover, the late endosomal/lysosomal cholesterol accumulation in LAMP(-/-) cells was diminished by overexpression of any of the three isoforms of LAMP-2, but not by LAMP-1. The LAMP-2 luminal domain, the membrane-proximal half in particular, was necessary and sufficient for the rescue effect. Taken together, our results suggest that LAMP-2, its luminal domain in particular, plays a critical role in endosomal cholesterol transport and that this is distinct from the chaperone-mediated autophagy function of LAMP-2.
AB - The mechanisms of endosomal and lysosomal cholesterol traffic are still poorly understood. We showed previously that unesterified cholesterol accumulates in the late endosomes and lysosomes of fibroblasts deficient in both lysosome associated membrane protein-2 (LAMP-2) and LAMP-1, two abundant membrane proteins of late endosomes and lysosomes. In this study we show that in cells deficient in both LAMP-1 and LAMP-2 (LAMP(-/-)), low-density lipoprotein (LDL) receptor levels and LDL uptake are increased as compared to wild-type cells. However, there is a defect in esterification of both endogenous and LDL cholesterol. These results suggest that LAMP(-/-) cells have a defect in cholesterol transport to the site of esterification in the endoplasmic reticulum, likely due to defective export of cholesterol out of late endosomes or lysosomes. We also show that cholesterol accumulates in LAMP-2 deficient liver and that overexpression of LAMP-2 retards the lysosomal cholesterol accumulation induced by U18666A. These results point to a critical role for LAMP-2 in endosomal/lysosomal cholesterol export. Moreover, the late endosomal/lysosomal cholesterol accumulation in LAMP(-/-) cells was diminished by overexpression of any of the three isoforms of LAMP-2, but not by LAMP-1. The LAMP-2 luminal domain, the membrane-proximal half in particular, was necessary and sufficient for the rescue effect. Taken together, our results suggest that LAMP-2, its luminal domain in particular, plays a critical role in endosomal cholesterol transport and that this is distinct from the chaperone-mediated autophagy function of LAMP-2.
KW - Animals
KW - Mice
KW - Protein Structure, Tertiary
KW - Cell Line
KW - Biological Transport
KW - Endoplasmic Reticulum/metabolism
KW - Endosomes/metabolism
KW - Cholesterol/metabolism
KW - Androstenes/pharmacology
KW - Lipoproteins, LDL/metabolism
KW - Lysosomal-Associated Membrane Protein 2/chemistry/genetics/metabolism
KW - Lysosome-Associated Membrane Glycoproteins/deficiency/metabolism
KW - Lysosomes/metabolism
KW - Membrane Proteins/metabolism
KW - Receptors, LDL/metabolism
KW - Animals
KW - Mice
KW - Protein Structure, Tertiary
KW - Cell Line
KW - Biological Transport
KW - Endoplasmic Reticulum/metabolism
KW - Endosomes/metabolism
KW - Cholesterol/metabolism
KW - Androstenes/pharmacology
KW - Lipoproteins, LDL/metabolism
KW - Lysosomal-Associated Membrane Protein 2/chemistry/genetics/metabolism
KW - Lysosome-Associated Membrane Glycoproteins/deficiency/metabolism
KW - Lysosomes/metabolism
KW - Membrane Proteins/metabolism
KW - Receptors, LDL/metabolism
U2 - 10.1111/j.1582-4934.2009.00973.x
DO - 10.1111/j.1582-4934.2009.00973.x
M3 - SCORING: Journal article
VL - 15
SP - 280
EP - 295
JO - J CELL MOL MED
JF - J CELL MOL MED
SN - 1582-1838
IS - 2
M1 - 2
ER -
