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Endoplasmic Reticulum-Plasma Membrane Contact Sites Integrate Sterol and Phospholipid Regulation

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Endoplasmic Reticulum-Plasma Membrane Contact Sites Integrate Sterol and Phospholipid Regulation RESEARCH ARTICLE Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation Evan Quon1☯, Yves Y. Sere2☯, Neha Chauhan2, Jesper Johansen1, David P. Sullivan2, Jeremy S. Dittman2, William J. Rice3, Robin B. Chan4, Gilbert Di Paolo4,5, Christopher T. Beh1,6*, Anant K. Menon2* 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada, 2 Department of Biochemistry, Weill Cornell Medical College, New York, New York, United States of a1111111111 America, 3 Simons Electron Microscopy Center at the New York Structural Biology Center, New York, New a1111111111 York, United States of America, 4 Department of Pathology and Cell Biology, Columbia University College of a1111111111 Physicians and Surgeons, New York, New York, United States of America, 5 Denali Therapeutics, South San a1111111111 Francisco, California, United States of America, 6 Centre for Cell Biology, Development, and Disease, Simon a1111111111 Fraser University, Burnaby, British Columbia, Canada ☯ These authors contributed equally to this work. * [email protected] (AKM); [email protected] (CTB) OPEN ACCESS Abstract Citation: Quon E, Sere YY, Chauhan N, Johansen J, Sullivan DP, Dittman JS, et al. (2018) Endoplasmic Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation. PLoS creating contact sites that are proposed to form platforms for regulating lipid homeostasis Biol 16(5): e2003864. https://doi.org/10.1371/ and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and trans- journal.pbio.2003864 ported by non-vesicular mechanisms to the plasma membrane (PM), where they represent Academic Editor: Sandra Schmid, UT almost half of all PM lipids and contribute critically to the barrier function of the PM. To deter- Southwestern Medical Center, United States of mine whether contact sites are important for both sterol exchange between the ER and PM America and intermembrane regulation of lipid metabolism, we generated Δ-super-tether (Δ-s-tether) Received: August 7, 2017 yeast cells that lack six previously identified tethering proteins (yeast extended synatotag- Accepted: April 20, 2018 min [E-Syt], vesicle-associated membrane protein [VAMP]-associated protein [VAP], and Published: May 21, 2018 TMEM16-anoctamin homologues) as well as the presumptive tether Ice2. Despite the lack of ER-PM contacts in these cells, ER-PM sterol exchange is robust, indicating that the sterol Copyright: © 2018 Quon et al. This is an open access article distributed under the terms of the transport machinery is either absent from or not uniquely located at contact sites. Unexpect- Creative Commons Attribution License, which edly, we found that the transport of exogenously supplied sterol to the ER occurs more permits unrestricted use, distribution, and slowly in Δ-s-tether cells than in wild-type (WT) cells. We pinpointed this defect to changes reproduction in any medium, provided the original in sterol organization and transbilayer movement within the PM bilayer caused by phospho- author and source are credited. lipid dysregulation, evinced by changes in the abundance and organization of PM lipids. Data Availability Statement: All relevant data are Indeed, deletion of either OSH4, which encodes a sterol/phosphatidylinositol-4-phosphate within the paper and its Supporting information files, specifically S1_Data.xlsx. (PI4P) exchange protein, or SAC1, which encodes a PI4P phosphatase, caused synthetic lethality in Δ-s-tether cells due to disruptions in redundant PI4P and phospholipid regulatory Funding: Qatar National Research Fund https:// www.qnrf.org/en-us/Funding/Research-Programs/ pathways. The growth defect of Δ-s-tether cells was rescued with an artificial "ER-PM sta- National-Priorities-Research-Program-NPRP (grant ple," a tether assembled from unrelated non-yeast protein domains, indicating that endoge- number NPRP 7 - 082 - 1 - 014). Received by nous tether proteins have nonspecific bridging functions. Finally, we discovered that sterols AKM. The funder had no role in study design, data collection and analysis, decision to publish, or play a role in regulating ER-PM contact site formation. In sterol-depleted cells, levels of the preparation of the manuscript. Discovery Grant and yeast E-Syt tether Tcb3 were induced and ER-PM contact increased dramatically. These PLOS Biology | https://doi.org/10.1371/journal.pbio.2003864 May 21, 2018 1 / 41 Lipid regulation at ER-plasma membrane contact sites Accelerator Supplement from the Natural Sciences results support a model in which ER-PM contact sites provide a nexus for coordinating the and Engineering Research Council (NSERC) of complex interrelationship between sterols, sphingolipids, and phospholipids that maintain Canada. Received by CTB. The funder had no role in study design, data collection and analysis, PM composition and integrity. decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Author summary Abbreviations: δ-ALA, δ-aminolevulinic acid; Δ-s- Almost half of the inner surface area of the yeast plasma membrane (PM) is covered with tether, Δ-super-tether; ABC, ATP-binding cassette; closely associated cortical endoplasmic reticulum (ER). In yeast and human cells, it has ACAT, acetyl-CoA acetyltransferase; ADP, adenosine diphosphate; CDP-DAG, cytidine been proposed that ER-anchored tether proteins staple the ER to the PM, creating mem- diphosphate DAG; CE, cholesteryl ester; cER, brane contact sites at which lipid transport between the ER and PM and membrane lipid cortical ER; CPYÃ, carboxypeptidase YÃ; cpm, synthesis are coordinately regulated, but the potential mechanisms are unclear. Here, we counts per minute; CTCF, corrected total cell test this idea by creating yeast cells that lack all ER-PM tethers. We find that whereas the fluorescence; C2, protein kinase C conserved bidirectional transport of sterols between the ER and PM is unaffected in these cells, ste- region 2; DAG, diacylglycerol; DHE, rols within the PM are disorganized due to disruptions in phospholipid biosynthesis that dehydroergosterol; DIC, differential interference contrast; DIM, detergent-insoluble membrane; ER, alter PM lipid composition. In particular, we show that phosphatidylinositol-4-phosphate, endoplasmic reticulum; ERAD, ER-associated a phospholipid needed for intracellular signaling and membrane trafficking, accumulates degradation; Erg9, squalene synthase; E-Syt, within the PM. Some of these defects can be rescued by reinstating membrane contacts extended synaptotagmin; FFAT, two phenylalanines via expression of an artificial tether. However, correction is also achieved without the crea- in an acidic tract; FIB-SEM, focused ion beam- tion of contacts by supplementing the growth medium with a precursor of membrane scanning electron microscope; GFP, green fluorescent protein; HPLC, high-performance liquid phospholipids. Based on these results, we propose that ER-PM contacts do not play a chromatography; IPC, inositol-phosphoceramide; major role as physical conduits for lipid exchange but rather serve as regulatory interfaces Lam, lipid transfer proteins anchored at MCSs; to integrate lipid synthesis pathways. MβCD, methyl-β-cyclodextrin; MCS, membrane contact site; MIPC, mannosylinositol phosphoceramide; mmPE, dimethyl PE; mPE, monomethyl PE; MRM, multiple reaction monitoring; MSP, major sperm protein; OSBP, Introduction oxysterol-binding protein; Osh, OSBP homologue; Most lipids are synthesized in the endoplasmic reticulum (ER) and distributed to other mem- PA, phosphatidic acid; PC, phosphatidylcholine; branes by non-vesicular mechanisms. These mechanisms act in conjunction with lipid meta- PCe, ether phosphatidylcholine; PE, bolic networks to maintain the unique lipid profile of the plasma membrane (PM) and phosphatidylethanolamine; PG, phosphatidylglycerol; PH, Pleckstrin homology; PI, subcellular organelles, and enable rapid membrane lipid remodeling in response to signals and phosphatidylinositol; PIP, phosphatidylinositol stresses [1±3]. An attractive hypothesis is that non-vesicular lipid transport and lipid biosyn- phosphate; PI4P, phosphatidylinositol-4- thetic and regulatory pathways intersect at ER-PM membrane contact sites (MCSs), where phosphate; PM, plasma membrane; PS, protein tethers retain the ER and PM within about 15±60 nm of each other [4±9]. In this view, phosphatidylserine; RFP, red fluorescent protein; ER-PM MCSs would serve as a nexus, coordinating requirements in the PM for lipids with RitC, C-terminal polybasic region from mammalian Rit1; RSR, relative specific radioactivity; SMP, their production in the ER [3, 9]. How this coordination is accomplished is not well under- synaptotagmin-like mitochondrial-lipid-binding stood. Here, we report on the interplay between sterol and phospholipid homeostasis at protein; SPOTS complex, SPT-Orm1/2-Tsc3-Sac1 ER-PM MCSs. complex; SR, specific radioactivity; StAR, CholesterolÐand its yeast counterpart ergosterolÐare synthesized in the ER and trans- steroidogenic acute regulatory; StART, ported by non-vesicular mechanisms to the PM [10, 11], where they are found at high concen- steroidogenic acute regulatory protein±related lipid trations corresponding to about 40 mole percent of PM lipids, i.e., one out of every two to transfer; STP, sterol transport protein; Tcb, tricalbin;
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