John A. Bowden, Alan Heckert, Candice Z. Ulmer, Christina M. Jones, Jeremy P. Koelmel, Laila Abdullah, Linda Ahonen, Yazen Alnouti, Aaron M. Armando, John M. Asara, Takeshi Bamba, John R. Barr, Jonas Bergquist, Christoph H. Borchers, Joost Brandsma, Susanne B. Breitkopf, Tomas Cajka, Amaury Cazenave-Gassiot, Antonio Checa, Michelle A. Cinel, Romain A. Colas, Serge Cremers, Edward A. Dennis, James E. Evans, Alexander Fauland, Oliver Fiehn, Michael S. Gardner, Timothy J. Garrett, Katherine H. Gotlinger, Jun Han, Yingying Huang, Aveline Huipeng Neo, Tuulia Hyötyläinen, Yoshihiro Izumi, Hongfeng Jiang, Houli Jiang, Jiang Jiang, Maureen Kachman, Reiko Kiyonami, Kristaps Klavins, Christian Klose, Harald C. Köfeler, Johan Kolmert, Therese Koal, Grielof Koster, Zsuzsanna Kuklenyik, Irwin J. Kurland, Michael Leadley, Karen Lin, Krishna Rao Maddipati, Danielle McDougall, Peter J. Meikle, Natalie A. Mellett, Cian Monnin, M. Arthur Moseley, Renu Nandakumar, Matej Oresic, Rainey Patterson, David Peake, Jason S. Pierce, Martin Post, Anthony D. Postle, Rebecca Pugh, Yunping Qiu, Oswald Quehenberger, Parsram Ramrup, Jon Rees, Barbara Rembiesa, Denis Reynaud, Mary R. Roth, Susanne Sales, Kai Schuhmann, Michal Laniado Schwartzman, Charles N. Serhan, Andrej Shevchenko, Stephen E. Somerville, Lisa St. John-Williams, Michal A. Surma, Hiroaki Takeda, Rhishikesh Thakare, J. Will Thompson, Federico Torta, Alexander Triebl, Martin Trötzmüller, S. J. Kumari Ubhayasekera, Dajana Vuckovic, Jacquelyn M. Weir, Ruth Welti, Markus R. Wenk, Craig E. Wheelock, Libin Yao, Min Yuan, Xueqing Heather Zhao, Senlin Zhou

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 the accessibility of PM cholesterol 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 to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.