Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex
- Nanyang Technological University, Singapore
- National University of Singapore, Singapore
- Kumamoto University, Japan
Abstract
Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor PM cholesterol accessibility remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind one another and populate at ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via GRAM domains and facilitate its transport via StART-like domains. Cells lacking all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol due to less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate movement of accessible PM cholesterol to the ER in order to counteract acute increase of PM cholesterol, activating non-vesicular cholesterol transport.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4, 5, 6, 7, 3-S-1, 3-S-2, 4-S-2, 4-S-3, 5-S-1, 5-S-2, 6-S-1, 6-S-2, 7-S-1, and 7-S-2.
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The structure of mouse AsterA (GramD1a) with 25-hydroxy cholesterolProtein Data Bank, 6GQF.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (17H05065)
- Yasunori Saheki
Ministry of Education - Singapore (MOE2017-T2-2-001)
- Yasunori Saheki
Nanyang Technological University (Nanyang Assistant Professorship (NAP))
- Yasunori Saheki
Nanyang Technological University (Lee Kong Chian School of Medicine startup grant)
- Yasunori Saheki
National Research Foundation Singapore (NRFI2015-05)
- Alexander Triebl
- Federico Tesio Torta
- Markus R Wenk
National Research Foundation Singapore (NRFSBP-P4)
- Alexander Triebl
- Federico Tesio Torta
- Markus R Wenk
Japan Society for the Promotion of Science (Overseas Research Fellowship)
- Tomoki Naito
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arun Radhakrishnan, University of Texas Southwestern Medical Center, United States
Version history
- Received: August 27, 2019
- Accepted: November 13, 2019
- Accepted Manuscript published: November 14, 2019 (version 1)
- Version of Record published: December 11, 2019 (version 2)
Copyright
© 2019, Naito et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex
eLife 8:e51401.
https://doi.org/10.7554/eLife.51401
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