Abstract
The endoplasmic reticulum (ER) possesses multiplicity of functions including protein synthesis, membrane lipid biogenesis, and Ca2+ storage and has broad localization throughout the cell. While the ER and most other membranous organelles are highly interconnected via vesicular traffic that relies on membrane budding and fusion reactions, the ER forms direct contacts with virtually all other membranous organelles, including the plasma membrane (PM), without membrane fusion. Growing evidence suggests that these contacts play major roles in cellular physiology, including the regulation of Ca2+ homeostasis and signaling and control of cellular lipid homeostasis. Extended synaptotagmins (E-Syts) are evolutionarily conserved family of ER-anchored proteins that tether the ER to the PM in PM PI(4,5)P2-dependent and cytosolic Ca2+-regulated manner. In addition, E-Syts possess a cytosolically exposed lipid-harboring module that confers the ability to transfer/exchange glycerolipids between the ER and the PM at E-Syts-mediated ER-PM contacts. In this chapter, the functions of ER-PM contacts and their role in non-vesicular lipid transport with special emphasis on the crosstalk between the two bilayers mediated by E-Syts will be discussed.
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References
Aguilar PS, Engel A, Walter P (2007) The plasma membrane proteins Prm1 and Fig1 ascertain fidelity of membrane fusion during yeast mating. Mol Biol Cell 18:547–556
AhYoung AP, Jiang J, Zhang J, Khoi Dang X, Loo JA, Zhou ZH, Egea PF (2015) Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly. Proc Natl Acad Sci USA 112:E3179–E3188
Alva V, Lupas AN (2016) The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport. Biochim Biophys Acta 1861:913–923
Beamer LJ, Carroll SF, Eisenberg D (1997) Crystal structure of human BPI and two bound phospholipids at 2.4 angstrom resolution. Science 276:1861–1864
Blackstone C, O’Kane CJ, Reid E (2011) Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 12:31–42
Braithwaite SP, Paul S, Nairn AC, Lombroso PJ (2006) Synaptic plasticity: one STEP at a time. Trends Neurosci 29:452–458
Chang CL, Liou J (2015) Phosphatidylinositol 4,5-Bisphosphate homeostasis regulated by Nir2 and Nir3 proteins at endoplasmic reticulum-plasma membrane junctions. J Biol Chem 290:14289–14301
Chang CL, Hsieh TS, Yang TT, Rothberg KG, Azizoglu DB, Volk E, Liao JC, Liou J (2013) Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell Rep 5:813–825
Chapman ER (2008) How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem 77:615–641
Chiapparino A, Maeda K, Turei D, Saez-Rodriguez J, Gavin AC (2016) The orchestra of lipid-transfer proteins at the crossroads between metabolism and signaling. Prog Lipid Res 61:30–39
Chung J, Torta F, Masai K, Lucast L, Czapla H, Tanner LB, Narayanaswamy P, Wenk MR, Nakatsu F, De Camilli P (2015) PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349:428–432
Cockcroft S, Garner K, Yadav S, Gomez-Espinoza E, Raghu P (2016) RdgBα reciprocally transfers PA and PI at ER-PM contact sites to maintain PI(4,5)P2 homoeostasis during phospholipase C signalling in Drosophila photoreceptors. Biochem Soc Trans 44:286–292
Craxton M (2001) Genomic analysis of synaptotagmin genes. Genomics 77:43–49
Craxton M (2007) Evolutionary genomics of plant genes encoding N-terminal-TM-C2 domain proteins and the similar FAM62 genes and synaptotagmin genes of metazoans. BMC Genom 8:259
Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296
Dickson EJ, Jensen JB, Vivas O, Kruse M, Traynor-Kaplan AE, Hille B (2016) Dynamic formation of ER-PM junctions presents a lipid phosphatase to regulate phosphoinositides. J Cell Biol 213:33–48
Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, De Camilli P (2016) Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166:408–423
Elbaz Y, Schuldiner M (2011) Staying in touch: the molecular era of organelle contact sites. Trends Biochem Sci 36:616–623
Fernandez-Busnadiego R, Saheki Y, De Camilli P (2015) Three-dimensional architecture of extended synaptotagmin-mediated endoplasmic reticulum-plasma membrane contact sites. Proc Natl Acad Sci USA 112(16):E2004-13
Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185
Friedman JR, Voeltz GK (2011) The ER in 3D: a multifunctional dynamic membrane network. Trends Cell Biol 21:709–717
Gallo A, Vannier C, Galli T (2016) Endoplasmic reticulum-plasma membrane associations:structures and functions. Annu Rev Cell Dev Biol 32:279–301
Gatta AT, Wong LH, Sere YY, Calderon-Norena DM, Cockcroft S, Menon AK, Levine TP (2015) A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport. Elife 4
Giordano F, Saheki Y, Idevall-Hagren O, Colombo SF, Pirruccello M, Milosevic I, Gracheva EO, Bagriantsev SN, Borgese N, De Camilli P (2013) PI(4,5)P2-dependent and Ca2+-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153:1494–1509
Helle SC, Kanfer G, Kolar K, Lang A, Michel AH, Kornmann B (2013) Organization and function of membrane contact sites. Biochim Biophys Acta 1833:2526–2541
Herdman C, Moss T (2016) Extended-Synaptotagmins (E-Syts); the extended story. Pharmacol Res 107:48–56
Holthuis JC, Levine TP (2005) Lipid traffic: floppy drives and a superhighway. Nat Rev Mol Cell Biol 6:209–220
Holthuis JC, Menon AK (2014) Lipid landscapes and pipelines in membrane homeostasis. Nature 510:48–57
Idevall-Hagren O, Lu A, Xie B, De Camilli P (2015) Triggered Ca2+ influx is required for extended synaptotagmin 1-induced ER-plasma membrane tethering. EMBO J 34:2291–2305
Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L et al (2015) Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca2+ influx. Nat Cell Biol 17:1339–1347
Kim YJ, Guzman-Hernandez ML, Wisniewski E, Balla T (2015) Phosphatidylinositol-phosphatidic acid exchange by Nir2 at ER-PM contact sites maintains phosphoinositide signaling competence. Dev Cell 33:549–561
Kopec KO, Alva V, Lupas AN (2010) Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria. Bioinformatics 26:1927–1931
Kopec KO, Alva V, Lupas AN (2011) Bioinformatics of the TULIP domain superfamily. Biochem Soc Trans 39:1033–1038
Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325:477–481
Lev S, Ben Halevy D, Peretti D, Dahan N (2008) The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol 18:282–290
Levy A, Zheng JY, Lazarowitz SG (2015) Synaptotagmin SYTA forms ER-plasma membrane junctions that are recruited to plasmodesmata for plant virus movement. Curr Biol 25:2018–2025
Lewis RS (2007) The molecular choreography of a store-operated calcium channel. Nature 446:284–287
Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241
Maeda K, Anand K, Chiapparino A, Kumar A, Poletto M, Kaksonen M, Gavin AC (2013) Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins. Nature 501:257–261
Manford AG, Stefan CJ, Yuan HL, Macgurn JA, Emr SD (2012) ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology. Dev Cell 23:1129–1140
Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, Antonny B (2013) A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155:830–843
Metuzals J, Chang D, Hammar K, Reese TS (1997) Organization of the cortical endoplasmic reticulum in the squid giant axon. J Neurocytol 26:529–539
Min SW, Chang WP, Sudhof TC (2007) E-Syts, a family of membranous Ca2+-sensor proteins with multiple C2 domains. Proc Natl Acad Sci USA 104:3823–3828
Moser von Filseck J, Copic A, Delfosse V, Vanni S, Jackson CL, Bourguet W, Drin G (2015) Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349:432–436
Murphy SE, Levine TP (2016) VAP, a versatile access point for the endoplasmic reticulum: review and analysis of FFAT-like motifs in the VAPome. Biochim Biophys Acta 1861:952–961
Neumann B, Coakley S, Giordano-Santini R, Linton C, Lee ES, Nakagawa A, Xue D, Hilliard MA (2015) EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517:219–222
Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L et al (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343:506–511
Omnus DJ, Manford AG, Bader JM, Emr SD, Stefan CJ (2016) Phosphoinositide kinase signaling controls ER-PM cross-talk. Mol Biol Cell 27:1170–1180
Orci L, Ravazzola M, Le Coadic M, Shen WW, Demaurex N, Cosson P (2009) From the Cover: STIM1-induced precortical and cortical subdomains of the endoplasmic reticulum. Proc Natl Acad Sci USA 106:19358–19362
Perez-Sancho J, Vanneste S, Lee E, McFarlane HE, Esteban Del Valle A, Valpuesta V, Friml J, Botella MA, Rosado A (2015) The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses. Plant Physiol 168:132–143
Perez-Sancho J, Tilsner J, Samuels AL, Botella MA, Bayer EM, Rosado A (2016) Stitching organelles: organization and function of specialized membrane contact sites in plants. Trends Cell Biol 26:705–717
Perni S, Dynes JL, Yeromin AV, Cahalan MD, Franzini-Armstrong C (2015) Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proc Natl Acad Sci USA 112:E5533–E5542
Phillips MJ, Voeltz GK (2016) Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol 17:69–82
Pichler H, Gaigg B, Hrastnik C, Achleitner G, Kohlwein SD, Zellnig G, Perktold A, Daum G (2001) A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids. Eur J Biochem 268:2351–2361
Porter KR, Palade GE (1957) Studies on the endoplasmic reticulum. III. Its form and distribution in striated muscle cells. J Biophys Biochem Cytol 3:269–300
Prinz WA (2014) Bridging the gap: Membrane contact sites in signaling, metabolism, and organelle dynamics. J Cell Biol 205:759–769
Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF et al (2007) Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 14:106–113
Quintana A, Rajanikanth V, Farber-Katz S, Gudlur A, Zhang C, Jing J, Zhou Y, Rao A, Hogan PG (2015) TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling. Proc Natl Acad Sci USA 112:E7083–E7092
Reinisch KM, De Camilli P (2016) SMP-domain proteins at membrane contact sites: Structure and function. Biochim Biophys Acta 1861:924–927
Rosenbluth J (1962) Subsurface cisterns and their relationship to the neuronal plasma membrane. J Cell Biol 13:405–421
Saheki Y, De Camilli P (2012) Synaptic vesicle endocytosis. Cold Spring Harb Perspect Biol 4:a005645
Saheki Y, Bian X, Schauder CM, Sawaki Y, Surma MA, Klose C, Pincet F, Reinisch KM, De Camilli P (2016) Control of plasma membrane lipid homeostasis by the extended synaptotagmins. Nat Cell Biol 18:504–515
Schapire AL, Voigt B, Jasik J, Rosado A, Lopez-Cobollo R, Menzel D, Salinas J, Mancuso S, Valpuesta V, Baluska F et al (2008) Arabidopsis synaptotagmin 1 is required for the maintenance of plasma membrane integrity and cell viability. Plant Cell 20:3374–3388
Schauder CM, Wu X, Saheki Y, Narayanaswamy P, Torta F, Wenk MR, De Camilli P, Reinisch KM (2014) Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer. Nature 510:552–555
Sclip A, Bacaj T, Giam LR, Sudhof TC (2016) Extended synaptotagmin (ESyt) triple knock-out mice are viable and fertile without obvious endoplasmic reticulum dysfunction. PLoS One 11:e0158295
Singleton A, Hardy J (2016) The evolution of genetics: Alzheimer’s and Parkinson’s diseases. Neuron 90:1154–1163
Small SA, Petsko GA (2015) Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci 16:126–132
Spacek J, Harris KM (1997) Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci 17:190–203
Stefan CJ, Manford AG, Baird D, Yamada-Hanff J, Mao Y, Emr SD (2011) Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites. Cell 144:389–401
Stuible M, Tremblay ML (2010) In control at the ER: PTP1B and the down-regulation of RTKs by dephosphorylation and endocytosis. Trends Cell Biol 20:672–679
Sudhof TC (2002) Synaptotagmins: why so many? J Biol Chem 277:7629–7632
Sudhof TC (2012) Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol 4:a011353
Tavassoli S, Chao JT, Young BP, Cox RC, Prinz WA, de Kroon AI, Loewen CJ (2013) Plasma membrane--endoplasmic reticulum contact sites regulate phosphatidylcholine synthesis. EMBO Rep 14:434–440
Toulmay A, Prinz WA (2011) Lipid transfer and signaling at organelle contact sites: the tip of the iceberg. Curr Opin Cell Biol 23:458–463
Toulmay A, Prinz WA (2012) A conserved membrane-binding domain targets proteins to organelle contact sites. J Cell Sci 125:49–58
Tremblay MG, Moss T (2016) Loss of all 3 extended synaptotagmins does not affect normal mouse development, viability or fertility. Cell Cycle 15:2360–2366
Varnai P, Toth B, Toth DJ, Hunyady L, Balla T (2007) Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 Complex. J Biol Chem 282:29678–29690
Weiss J (2003) Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP): structure, function and regulation in host defence against Gram-negative bacteria. Biochem Soc Trans 31:785–790
West M, Zurek N, Hoenger A, Voeltz GK (2011) A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature. J Cell Biol 193:333–346
Xu J, Bacaj T, Zhou A, Tomchick DR, Sudhof TC, Rizo J (2014) Structure and Ca2+-binding properties of the tandem C(2) domains of E-Syt2. Structure 22:269–280
Yadav S, Garner K, Georgiev P, Li M, Gomez-Espinosa E, Panda A, Mathre S, Okkenhaug H, Cockcroft S, Raghu P (2015) RDGBα, a PtdIns-PtdOH transfer protein, regulates G-protein-coupled PtdIns(4,5)P2 signalling during Drosophila phototransduction. J Cell Sci 128:3330–3344
Yamazaki T, Kawamura Y, Minami A, Uemura M (2008) Calcium-dependent freezing tolerance in Arabidopsis involves membrane resealing via synaptotagmin SYT1. Plant Cell 20:3389–3404
Yu H, Liu Y, Gulbranson DR, Paine A, Rathore SS, Shen J (2016) Extended synaptotagmins are Ca2+-dependent lipid transfer proteins at membrane contact sites. Proc Natl Acad Sci USA 113:4362–4367
Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905
Zhang L, Yan F, Zhang S, Lei D, Charles MA, Cavigiolio G, Oda M, Krauss RM, Weisgraber KH, Rye KA et al (2012a) Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat Chem Biol 8:342–349
Zhang Y, Wang H, Kage-Nakadai E, Mitani S, Wang X (2012b) C. elegans secreted lipid-binding protein NRF-5 mediates PS appearance on phagocytes for cell corpse engulfment. Curr Biol 22:1276–1284
Acknowledgements
We apologize to all the investigators whose work could not be cited due to space limitations. We thank Pietro De Camilli for helpful suggestions. Work from the authors related to this review has been supported in part by a Nanyang Assistant Professorship grant (L0403050) and a Lee Kong Chian School of Medicine Start-up grant (L0412410), Nanyang Technological University, to Y.S.
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Saheki, Y. (2017). Endoplasmic Reticulum – Plasma Membrane Crosstalk Mediated by the Extended Synaptotagmins. In: Tagaya, M., Simmen, T. (eds) Organelle Contact Sites. Advances in Experimental Medicine and Biology, vol 997. Springer, Singapore. https://doi.org/10.1007/978-981-10-4567-7_6
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