27
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART-like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER.

          DOI: http://dx.doi.org/10.7554/eLife.07253.001

          eLife digest

          Membranes are crucial structures for cells that are made primarily of fat molecules. The most important membrane is the external one that surrounds cells and keeps the outside world out and cellular contents in. The single most common fat component in the external membrane is cholesterol, which makes the membrane rigid and better able to withstand the outside world. So even though excess cholesterol contributes to diseases such as heart disease, stroke and Alzheimer's, the external membrane of every cell needs about a billion cholesterol molecules for its normal function. But how do cells manage the traffic of these molecules to their destination?

          It is known that when external membranes are short of cholesterol they make it at a different cellular location. There is an internal network—called the endoplasmic reticulum—that spreads just about everywhere throughout the cell. This network is where fats like cholesterol are made when the cell has not got enough, and where they are converted into an inert form when the cell has too much. What is not known is how cholesterol moves to and fro between this network and the external membrane.

          One theory is that cholesterol and other fats move only where the internal network comes into close contact with the external membrane, without quite touching. This theory comes in part from the finding that many of the proteins found in the narrow gaps between the internal network and the external membrane are capable of transferring fats across the gap. However, one of the missing supports for this theory is that no protein that transfers cholesterol across this gap has been found.

          Gatta, Wong, Sere et al. used computational tools to scan the database of known proteins for those that might be able to transfer cholesterol, and found a new family of fat transfer proteins. Further experiments showed that these proteins only bind to cholesterol out of all the fats. Next, Gatta, Wong, Sere et al. studied what the proteins do in cells, but instead of looking at the proteins in human cells they studied the related proteins in yeast. This is because the details of both the traffic of cholesterol and contacts between the internal network and the external membrane are in many respects understood better in yeast than in human cells.

          Gatta, Wong, Sere et al. found the cholesterol transfer proteins were embedded in regions where the internal network was in close contact with the external membrane. Also, in cells that lacked these proteins, cholesterol added to the external membrane had difficulty transferring to the internal network.

          These results together suggest that the newly identified lipid transfer proteins exchange lipids between the plasma membrane and endoplasmic reticulum at membrane contact sites. Further research is required to understand in detail how these proteins work.

          DOI: http://dx.doi.org/10.7554/eLife.07253.002

          Related collections

          Most cited references60

          • Record: found
          • Abstract: found
          • Article: not found

          Lipid landscapes and pipelines in membrane homeostasis.

          The lipid composition of cellular organelles is tailored to suit their specialized tasks. A fundamental transition in the lipid landscape divides the secretory pathway in early and late membrane territories, allowing an adaptation from biogenic to barrier functions. Defending the contrasting features of these territories against erosion by vesicular traffic poses a major logistical problem. To this end, cells evolved a network of lipid composition sensors and pipelines along which lipids are moved by non-vesicular mechanisms. We review recent insights into the molecular basis of this regulatory network and consider examples in which malfunction of its components leads to system failure and disease.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Phospholipid synthesis in a membrane fraction associated with mitochondria.

            J Vance (1990)
            A crude rat liver mitochondrial fraction that was capable of the rapid, linked synthesis of phosphatidylserine (PtdSer), phosphatidylethanolamine (PtdEtn), and phosphatidylcholine (PtdCho) labeled from [3-3H] serine has been fractionated. PtdSer synthase, PtdEtn methyltransferase, and CDP-choline:diacylglycerol cholinephosphotransferase activities were present in the crude mitochondrial preparation but were absent from highly purified mitochondria and could be attributed to the presence of a membrane fraction, X. Thus, previous claims of the mitochondrial location of some of these enzymes might be explained by the presence of fraction X in the mitochondrial preparation. Fraction X had many similarities to microsomes except that it sedimented with mitochondria (at 10,000 x g). However, the specific activities of PtdSer synthase and glucose-6-phosphate phosphatase in fraction X were almost twice that of microsomes, and the specific activities of CTP:phosphocholine cytidylyltransferase and NADPH:cytochrome c reductase in fraction X were much lower than in microsomes. The marker enzymes for mitochondria, Golgi apparatus, plasma membrane, lysosomes, and peroxisomes all had low activities in fraction X. Polyacrylamide gel electrophoresis revealed distinct differences, as well as similarities, among the proteins of fraction X, microsomes, and rough and smooth endoplasmic reticulum. The combined mitochondria-fraction X membranes can synthesize PtdSer, PtdEtn, and PtdCho from serine. Thus, fraction X in combination with mitochondria might be responsible for the observed compartmentalization of a serine-labeled pool of phospholipids previously identified (Vance, J. E., and Vance, D. E. (1986) J. Biol. Chem. 261, 4486-4491) and might be involved in the transfer of lipids between the endoplasmic reticulum and mitochondria.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.

              Several proteins at endoplasmic reticulum (ER)-Golgi membrane contact sites contain a PH domain that interacts with the Golgi phosphoinositide PI(4)P, a FFAT motif that interacts with the ER protein VAP-A, and a lipid transfer domain. This architecture suggests the ability to both tether organelles and transport lipids between them. We show that in oxysterol binding protein (OSBP) these two activities are coupled by a four-step cycle. Membrane tethering by the PH domain and the FFAT motif enables sterol transfer by the lipid transfer domain (ORD), followed by back transfer of PI(4)P by the ORD. Finally, PI(4)P is hydrolyzed in cis by the ER protein Sac1. The energy provided by PI(4)P hydrolysis drives sterol transfer and allows negative feedback when PI(4)P becomes limiting. Other lipid transfer proteins are tethered by the same mechanism. Thus, OSBP-mediated back transfer of PI(4)P might coordinate the transfer of other lipid species at the ER-Golgi interface. Copyright © 2013 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                2050-084X
                22 May 2015
                2015
                : 4
                : e07253
                Affiliations
                [1 ]deptDepartment of Cell Biology , UCL Institute of Ophthalmology , London, United Kingdom
                [2 ]deptDepartment of Biochemistry , Weill Cornell Medical College , New York, United States
                [3 ]deptDepartment of Neuroscience, Physiology and Pharmacology , University College London , London, United Kingdom
                Yale University , United States
                Yale University , United States
                Author notes
                [* ]For correspondence: tim.levine@ 123456ucl.ac.uk
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-2404-7351
                http://orcid.org/0000-0001-6924-2698
                Article
                07253
                10.7554/eLife.07253
                4463742
                26001273
                b2a05a0d-bf57-4c68-a82e-ef77cf398e8d
                © 2015, Gatta et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 27 February 2015
                : 20 May 2015
                Funding
                Funded by: Qatar National Research Fund (QNRF);
                Award ID: NPRP 5-669-1-112
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: MR/J006580/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: Sphingonet ITN, project ref 289278
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                2.3
                A new family of sterol-specific lipid transfer proteins has been found that anchors in the endoplasmic reticulum; some of these proteins stretch across membrane contacts and mediate sterol traffic from the plasma membrane.

                Life sciences
                membrane contact sites,lipid traffic,cholesterol,ergosterol,start protein,polyenes,vast domains,s. cerevisiae

                Comments

                Comment on this article