ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter
- 17 November 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (49), 19719-19724
- https://doi.org/10.1073/pnas.1113021108
Abstract
Four members of the mammalian ATP binding cassette (ABC) transporter G subfamily are thought to be involved in transmembrane (TM) transport of sterols. The residues responsible for this transport are unknown. The mechanism of action of ABCG1 is controversial and it has been proposed to act at the plasma membrane to facilitate the efflux of cellular sterols to exogenous high-density lipoprotein (HDL). Here we show that ABCG1 function is dependent on localization to intracellular endosomes. Importantly, localization to the endosome pathway distinguishes ABCG1 and/or ABCG4 from all other mammalian members of this superfamily, including other sterol transporters. We have identified critical residues within the TM domains of ABCG1 that are both essential for sterol transport and conserved in some other members of the ABCG subfamily and/or the insulin-induced gene 2 (INSIG-2). Our conclusions are based on studies in which (i) biotinylation of peritoneal macrophages showed that endogenous ABCG1 is intracellular and undetectable at the cell surface, (ii) a chimeric protein containing the TM of ABCG1 and the cytoplasmic domains of the nonsterol transporter ABCG2 is both targeted to endosomes and functional, and (iii) ABCG1 colocalizes with multiple proteins that mark late endosomes and recycling endosomes. Mutagenesis studies identify critical residues in the TM domains that are important for ABCG1 to alter sterol efflux, induce sterol regulatory element binding protein-2 (SREBP-2) processing, and selectively attenuate the oxysterol-mediated repression of SREBP-2 processing. Our data demonstrate that ABCG1 is an intracellular sterol transporter that localizes to endocytic vesicles to facilitate the redistribution of specific intracellular sterols away from the endoplasmic reticulum (ER).Keywords
This publication has 43 references indexed in Scilit:
- An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cellsJCI Insight, 2010
- Impaired Development of Atherosclerosis in Abcg1 −/− Apoe −/− MiceArteriosclerosis, Thrombosis, and Vascular Biology, 2010
- Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol effluxJournal of Lipid Research, 2009
- Emerging new paradigms for ABCG transportersBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
- Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate BalanceCell Metabolism, 2008
- Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in miceJCI Insight, 2007
- High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1Proceedings of the National Academy of Sciences of the United States of America, 2007
- Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to InsigProceedings of the National Academy of Sciences of the United States of America, 2007
- AAA+ proteins: have engine, will workNature Reviews Molecular Cell Biology, 2005
- Cholesterol and 25-Hydroxycholesterol Inhibit Activation of SREBPs by Different Mechanisms, Both Involving SCAP and InsigsPublished by Elsevier BV ,2004