Cargando…

NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining atte...

Descripción completa

Detalles Bibliográficos
Autores principales: Höglinger, D., Burgoyne, T., Sanchez-Heras, E., Hartwig, P., Colaco, A., Newton, J., Futter, C. E., Spiegel, S., Platt, F. M., Eden, E. R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753064/
https://www.ncbi.nlm.nih.gov/pubmed/31537798
http://dx.doi.org/10.1038/s41467-019-12152-2
_version_ 1783452818125881344
author Höglinger, D.
Burgoyne, T.
Sanchez-Heras, E.
Hartwig, P.
Colaco, A.
Newton, J.
Futter, C. E.
Spiegel, S.
Platt, F. M.
Eden, E. R
author_facet Höglinger, D.
Burgoyne, T.
Sanchez-Heras, E.
Hartwig, P.
Colaco, A.
Newton, J.
Futter, C. E.
Spiegel, S.
Platt, F. M.
Eden, E. R
author_sort Höglinger, D.
collection PubMed
description Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.
format Online
Article
Text
id pubmed-6753064
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-67530642019-09-23 NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress Höglinger, D. Burgoyne, T. Sanchez-Heras, E. Hartwig, P. Colaco, A. Newton, J. Futter, C. E. Spiegel, S. Platt, F. M. Eden, E. R Nat Commun Article Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells. Nature Publishing Group UK 2019-09-19 /pmc/articles/PMC6753064/ /pubmed/31537798 http://dx.doi.org/10.1038/s41467-019-12152-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Höglinger, D.
Burgoyne, T.
Sanchez-Heras, E.
Hartwig, P.
Colaco, A.
Newton, J.
Futter, C. E.
Spiegel, S.
Platt, F. M.
Eden, E. R
NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title_full NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title_fullStr NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title_full_unstemmed NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title_short NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
title_sort npc1 regulates er contacts with endocytic organelles to mediate cholesterol egress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753064/
https://www.ncbi.nlm.nih.gov/pubmed/31537798
http://dx.doi.org/10.1038/s41467-019-12152-2
work_keys_str_mv AT hoglingerd npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT burgoynet npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT sanchezherase npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT hartwigp npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT colacoa npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT newtonj npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT futterce npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT spiegels npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT plattfm npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress
AT edener npc1regulatesercontactswithendocyticorganellestomediatecholesterolegress