Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
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Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export. / Heybrock, Saskia; Kanerva, Kristiina; Meng, Ying; Ing, Chris; Liang, Anna; Xiong, Zi-Jian; Weng, Xialian; Ah Kim, Young; Collins, Richard; Trimble, William; Pomès, Régis; Privé, Gilbert G; Annaert, Wim; Schwake, Michael; Heeren, Joerg; Lüllmann-Rauch, Renate; Grinstein, Sergio; Ikonen, Elina; Saftig, Paul; Neculai, Dante.
in: NAT COMMUN, Jahrgang 10, Nr. 1, 06.08.2019, S. 3521.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
AU - Heybrock, Saskia
AU - Kanerva, Kristiina
AU - Meng, Ying
AU - Ing, Chris
AU - Liang, Anna
AU - Xiong, Zi-Jian
AU - Weng, Xialian
AU - Ah Kim, Young
AU - Collins, Richard
AU - Trimble, William
AU - Pomès, Régis
AU - Privé, Gilbert G
AU - Annaert, Wim
AU - Schwake, Michael
AU - Heeren, Joerg
AU - Lüllmann-Rauch, Renate
AU - Grinstein, Sergio
AU - Ikonen, Elina
AU - Saftig, Paul
AU - Neculai, Dante
PY - 2019/8/6
Y1 - 2019/8/6
N2 - The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol-like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.
AB - The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol-like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.
KW - Animals
KW - CD36 Antigens/genetics
KW - CHO Cells
KW - Carrier Proteins/genetics
KW - Cholesterol, LDL/metabolism
KW - Cricetulus
KW - Fibroblasts
KW - Gene Knockout Techniques
KW - HeLa Cells
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Lipid Droplets/metabolism
KW - Lysosome-Associated Membrane Glycoproteins/genetics
KW - Lysosomes/metabolism
KW - Membrane Glycoproteins/genetics
KW - Mice
KW - Protein Domains
KW - RNA, Small Interfering/metabolism
KW - Receptors, Scavenger/genetics
U2 - 10.1038/s41467-019-11425-0
DO - 10.1038/s41467-019-11425-0
M3 - SCORING: Journal article
C2 - 31387993
VL - 10
SP - 3521
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -