TY - JOUR
T1 - Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex
AU - Naito, Tomoki
AU - Ercan, Bilge
AU - Krshnan, Logesvaran
AU - Triebl, Alexander
AU - Koh, Dylan Hong Zheng
AU - Wei, Fan Yan
AU - Tomizawa, Kazuhito
AU - Torta, Federico Tesio
AU - Wenk, Markus R.
AU - Saheki, Yasunori
N1 - Funding Information:
We thank Pietro De Camilli, Min Wu, Luo Dahai, Darshini Jeyasimman, Jingbo Sun, Nur Raihanah Binte Mohd Harion and Dhakshenya Dhinagaran for discussion and/or sharing reagents. We thank the NTU Protein Production Platform (www.proteins.sg) for the cloning, expression tests and purification of wild-type StART-like domains of GRAMD1a, GRAMD1b, GRAMD1c and GRAM domains of GRAMD1a and GRAMD1b, and recombinant EGFP-D4 and EGFP-D4H proteins. This work was supported in part by the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2017-T2-2-001), a Nanyang Assistant Professorship (NAP), a Lee Kong Chian School of Medicine startup grant (LKCMedicine-SUG), and a Grant-in-Aid for Young Scientists (A) from the Japan Society for the Promotion of Science (17H05065) to Y.S. M.R.W., F.T.T. and A.T. were supported by grants from the National University of Singapore via the Life Sciences Institute (LSI) and the National Research Foundation (NRFI2015-05 and NRFSBP-P4). T.N. was supported by a fellowship from ethaJpanese oSciety rforo mPotion fo cieSnce.
Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.
PY - 2019/11
Y1 - 2019/11
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.51401
DO - 10.7554/eLife.51401
M3 - Article
C2 - 31724953
AN - SCOPUS:85076217976
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e51401
ER -