Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System
Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717306538 |
| _version_ | 1818989022016438272 |
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| author | Kexin Zhao Neale D. Ridgway |
| author_facet | Kexin Zhao Neale D. Ridgway |
| author_sort | Kexin Zhao |
| collection | DOAJ |
| description | Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP)-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles. |
| first_indexed | 2024-12-20T19:31:52Z |
| format | Article |
| id | doaj.art-7041239d5bf141eab0ab20101b33159a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T19:31:52Z |
| publishDate | 2017-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7041239d5bf141eab0ab20101b33159a2022-12-21T19:28:46ZengElsevierCell Reports2211-12472017-05-011991807181810.1016/j.celrep.2017.05.028Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal SystemKexin Zhao0Neale D. Ridgway1Departments of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Box 15000, Halifax, NS B3H 4R2, CanadaDepartments of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Box 15000, Halifax, NS B3H 4R2, CanadaLipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP)-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.http://www.sciencedirect.com/science/article/pii/S2211124717306538oxysterol-binding proteinscholesterol transportendoplasmic reticulumendosomes/lysosomesNPC1 |
| spellingShingle | Kexin Zhao Neale D. Ridgway Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System Cell Reports oxysterol-binding proteins cholesterol transport endoplasmic reticulum endosomes/lysosomes NPC1 |
| title | Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System |
| title_full | Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System |
| title_fullStr | Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System |
| title_full_unstemmed | Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System |
| title_short | Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System |
| title_sort | oxysterol binding protein related protein 1l regulates cholesterol egress from the endo lysosomal system |
| topic | oxysterol-binding proteins cholesterol transport endoplasmic reticulum endosomes/lysosomes NPC1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717306538 |
| work_keys_str_mv | AT kexinzhao oxysterolbindingproteinrelatedprotein1lregulatescholesterolegressfromtheendolysosomalsystem AT nealedridgway oxysterolbindingproteinrelatedprotein1lregulatescholesterolegressfromtheendolysosomalsystem |