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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·2019·Nature Communications
DOI 10.1038/s41467-019-12152-2PMC PMC6753064
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Abstract

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.

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  • Other studies provide evidence that cholesterol moves directly from lysosomes to the ER and other membranes.

    “Other studies have provided evidence indicating that cholesterol moves directly from lysosomes to the ER and other membranes (9–12).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [12]

    The Discussion (page not specified) presents evidence for direct cholesterol transport from endocytic organelles, including lysosomes, to the ER. It also mentions cholesterol transport to mitochondria and recycling to the plasma membrane, but does not establish direct transport from lysosomes to those other membranes. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 47

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Metadata

Authors
Höglinger, D., Burgoyne, T., Sanchez-Heras, E., Hartwig, P., Colaco, A., Newton, J., Futter, C. E., Spiegel, S., Platt, F. M., & Eden, E. R.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-09-19
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-12152-2
PMC
PMC6753064
Cited by
299
References
6
Language
en
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