Abstract
Lipids are distributed in a highly heterogeneous fashion in different cellular membranes. Only a minority of lipids achieve their final intracellular distribution through transport by vesicles. Instead, the bulk of lipid traffic is mediated by a large group of lipid transfer proteins (LTPs), which move small numbers of lipids at a time using hydrophobic cavities that stabilize lipid molecules outside membranes. Although the first LTPs were discovered almost 50 years ago, most progress in understanding these proteins has been made in the past few years, leading to considerable temporal and spatial refinement of our understanding of the function of these lipid transporters. The number of known LTPs has increased, with exciting discoveries of their multimeric assembly. Structural studies of LTPs have progressed from static crystal structures to dynamic structural approaches that show how conformational changes contribute to lipid handling at a sub-millisecond timescale. A major development has been the finding that many intracellular LTPs localize to two organelles at the same time, forming a shuttle, bridge or tube that links donor and acceptor compartments. The understanding of how different lipids achieve their final destination at the molecular level allows a better explanation of the range of defects that occur in diseases associated with lipid transport and distribution, opening up the possibility of developing therapies that specifically target lipid transfer.
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References
van Meer, G., Voelker, D. R. & Feigenson, G. W. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell. Biol. 9, 112–124 (2008).
Wirtz, K. W. a & Zilversmit, D. B. Exchange of phospholipids between liver mitochondria and microsomes in vitro. J. Biol. Chem. 243, 3596–3602 (1968).
Mari, M., Tooze, S. A. & Reggiori, F. The puzzling origin of the autophagosomal membrane. F1000 Biol. Rep. 3, 25 (2011).
Santos, A. X. S. & Riezman, H. Yeast as a model system for studying lipid homeostasis and function. FEBS Lett. 586, 2858–2867 (2012).
Holthuis, J. C. M. & Menon, A. K. Lipid landscapes and pipelines in membrane homeostasis. Nature 510, 48–57 (2014).
Kaplan, M. R. & Simoni, R. D. Transport of cholesterol from the endoplasmic reticulum to the plasma membrane. J. Cell Biol. 101, 446–453 (1985).
Urbani, L. & Simoni, R. D. Cholesterol and vesicular stomatitis virus G protein take separate routes from the endoplasmic reticulum to the plasma membrane. J. Biol. Chem. 265, 1919–1923 (1990).
Von Filseck, J. M. et al. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349, 432–436 (2015). This paper and reference 42 detail in vitro and in vivo experiments on the PtdSer and PtdIns(4)P counter-current transfer between ER (low PtdSer) and the plasma membrane (high PtdSer) by Osh6p/Osh7p in yeast and ORP5/Orp8 in humans. These studies cement counter-current as a general strategy employed by ORPs to move lipids against concentration gradients using a gradient of phosphoinositides in the opposite direction.
Vance, J. E., Aasman, E. J. & Szarka, R. Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites of synthesis to the cell surface. J. Biol. Chem. 266, 8241–8247 (1991).
Heino, S. et al. Dissecting the role of the Golgi complex and lipid rafts in biosynthetic transport of cholesterol to the cell surface. Proc. Natl Acad. Sci. USA 97, 8375–8380 (2000).
Baumann, N. A. et al. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration. Biochemistry 44, 5816–5826 (2005).
McLean, L. R. & Phillips, M. C. Kinetics of phosphatidylcholine and lysophosphatidylcholine exchange between unilamellar vesicles. Biochemistry 23, 4624–4630 (1984).
Dittman, J. S. & Menon, A. K. Speed limits for nonvesicular intracellular sterol transport. Trends Biochem. Sci. 42, 90–97 (2017).
Helmkamp, G. M., Harvey, M. S., Wirtz, K. W. & Van Deenen, L. L. Phospholipid exchange between membranes. Purification of bovine brain proteins that preferentially catalyze the transfer of phosphatidylinositol. J. Biol. Chem. 249, 6382–6389 (1974).
Sha, B., Phillips, S. E., Bankaitis, V. A. & Luo, M. Crystal structure of the Saccharomyces cerevisiae phosphatidylinositol-transfer protein. Nature 391, 506–510 (1998).
Tsujishita, Y. & Hurley, J. H. Structure and lipid transport mechanism of a StAR-related domain. Nat. Struct. Biol. 7, 408–414 (2000).
Chiapparino, A., Maeda, K., Turei, D., Saez-Rodriguez, J. & Gavin, A.-C. The orchestra of lipid-transfer proteins at the crossroads between metabolism and signaling. Prog. Lipid Res. 61, 30–39 (2016).
Schrick, K. et al. Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity. BMC Biol. 12, 70 (2014).
Malinverni, J. C. & Silhavy, T. J. An ABC transport system that maintains lipid asymmetry in the gram-negative outer membrane. Proc. Natl Acad. Sci. USA 106, 8009–8014 (2009).
Wong, L. H. & Levine, T. P. Lipid transfer proteins do their thing anchored at membrane contact sites… but what is their thing? Biochem. Soc. Trans. 44, 517–527 (2016).
Iaea, D. B., Dikiy, I., Kiburu, I., Eliezer, D. & Maxfield, F. R. STARD4 membrane interactions and sterol binding. Biochemistry 54, 4623–4636 (2015). This article presents a biophysical study of the mechanism of membrane interaction by STARD4 that unifies previous models on movement of either the carboxy-terminal helix or the Ω1 loop by showing that both move following membrane engagement by the LTP domain prior to lipid transfer.
Kudo, N. et al. Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc. Natl Acad. Sci. USA 105, 488–493 (2008).
Cockcroft, S. & Garner, K. Function of the phosphatidylinositol transfer protein gene family: is phosphatidylinositol transfer the mechanism of action? Crit. Rev. Biochem. Mol. Biol. 46, 89–117 (2011).
Garner, K. et al. Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid. J. Biol. Chem. 287, 32263–32276 (2012).
Schouten, A. et al. Structure of apo-phosphatidylinositol transfer protein alpha provides insight into membrane association. EMBO J. 21, 2117–2121 (2002).
Tilley, S. J. et al. Structure-function analysis of phosphatidylinositol transfer protein alpha bound to human phosphatidylinositol. Structure 12, 317–326 (2004).
Miliara, X. et al. Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes. EMBO Rep. 16, 824–835 (2015).
Watanabe, Y., Tamura, Y., Kawano, S. & Endo, T. Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria. Nat. Commun. 6, 7922 (2015).
Yu, F. et al. Structural basis of intramitochondrial phosphatidic acid transport mediated by Ups1-Mdm35 complex. EMBO Rep. 16, 813–823 (2015). The studies in references 27–29 provide crystal structures that confirm earlier predictions that PRELI domains (Ups1–Ups3 in yeast) are StARkin domains, which differ from all others in that they require transient dissociation of a small subunit (TRIAP1 in humans and Mdm35 in yeast) to allow lipid extraction upon membrane docking.
Aaltonen, M. J. et al. MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J. Cell Biol. 213, 525–534 (2016).
Connerth, M. et al. Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. Science 338, 815–818 (2012).
Aitken, J. F., Paul, G., Van Heusdens, H., Temkin, M. & Dowhang, W. The gene encoding the phosphatidylinositol transfer protein is essential for cell growth. J. Biol. Chem. 265, 4711–4717 (1990).
Gu, M., Warshawsky, I. & Majerus, P. W. Cloning and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to retinaldehyde-binding protein and yeast SEC14p. Proc. Natl Acad. Sci. USA 89, 2980–2984 (1992).
Huang, J. et al. Two-ligand priming mechanism for potentiated phosphoinositide synthesis is an evolutionarily conserved feature of Sec14-like phosphatidylinositol and phosphatidylcholine exchange proteins. Mol. Biol. Cell 27, 2317–2330 (2016).
Panagabko, C. et al. Ligand specificity in the CRAL-TRIO protein family. Biochemistry 42, 6467–6474 (2003).
Saari, J. C., Nawrot, M., Stenkamp, R. E., Teller, D. C. & Garwin, G. G. Release of 11-cis-retinal from cellular retinaldehyde-binding protein by acidic lipids. Mol. Vis. 15, 844–854 (2009).
Schaaf, G. et al. Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the Sec14 superfamily. Mol. Cell 29, 191–206 (2008).
Ryan, M. M., Temple, B. R. S., Phillips, S. E. & Bankaitis, V. A. Conformational dynamics of the major yeast phosphatidylinositol transfer protein sec14p: insight into the mechanisms of phospholipid exchange and diseases of sec14p-like protein deficiencies. Mol. Biol. Cell 18, 1928–1942 (2007).
de Saint-Jean, M. et al. Osh4p exchanges sterols for phosphatidylinositol 4-phosphate between lipid bilayers. J. Cell Biol. 195, 965–978 (2011). This breakthrough study uses real-time in vitro transfer assays and the crystal structure of Osh4p with PtdIns(4)P (which was not an expected ligand of Osh4p) to arrive at the first description of a lipid counter-current mechanism.
Mesmin, B., Antonny, B. & Drin, G. Insights into the mechanisms of sterol transport between organelles. Cell. Mol. Life Sci. 70, 3405–3421 (2013).
Maeda, K. et al. Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins. Nature 501, 257–261 (2013).
Chung, J. et al. PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349, 428–432 (2015). See note for reference 8.
Tong, J., Yang, H., Yang, H., Eom, S. H. & Im, Y. J. Structure of Osh3 reveals a conserved mode of phosphoinositide binding in oxysterol-binding proteins. Structure 21, 1203–1213 (2013).
Ghai, R. et al. ORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P2) and regulate its level at the plasma membrane Nat. Commun. 8, 757 (2017).
Raychaudhuri, S., Im, Y. J., Hurley, J. H. & Prinz, W. A. Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides. J. Cell Biol. 173, 107–119 (2006).
Insall, R. H. & Weiner, O. D. PIP3, PIP2, and cell movement — similar messages, different meanings? Dev. Cell 1, 743–747 (2001).
Suits, M. D. L., Sperandeo, P., Dehò, G., Polissi, A. & Jia, Z. Novel structure of the conserved Gram-negative lipopolysaccharide transport protein A and mutagenesis analysis. J. Mol. Biol. 380, 476–488 (2008). This study presents the structural basis of LPS transport between bacterial inner and outer membranes by Lpt oligomers that form a static bridge.
Tran, A. X., Dong, C. & Whitfield, C. Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli. J. Biol. Chem. 285, 33529–33539 (2010).
Botos, I. et al. Structural and functional characterization of the LPS transporter LptDE from Gram-negative pathogens. Structure 24, 965–976 (2016).
Wong, L. H. & Levine, T. P. Tubular lipid binding proteins (TULIPs) growing everywhere. Biochim. Biophys. Acta 1864, 1439–1449 (2017).
Zhang, L. et al. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat. Chem. Biol. 8, 342–349 (2012).
Tall, A. R. & Rader, D. J. Trials and tribulations of CETP inhibitors. Circul. Res. 122, 106–112 (2018).
Qiu, X. et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat. Struct. Mol. Biol. 14, 106–113 (2007).
Lauer, M. E. et al. Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP. J. Struct. Biol. 194, 191–198 (2016).
Kopec, K. O., Alva, V. & Lupas, A. N. 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 (2010). This study presents the first use of remote homology searches to predict new LTPs. The TULIP superfamily is expanded to include SMP domains as intracellular counterparts of extracellular LTPs in the BPI–CETP–PLTP family.
Schauder, C. M. et al. Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer. Nature 510, 552–555 (2014).
AhYoung, A. P., Lu, B., Cascio, D. & Egea, P. F. Crystal structure of Mdm12 and combinatorial reconstitution of Mdm12/Mmm1 ERMES complexes for structural studies. Biochem. Biophys. Res. Commun. 488, 129–135 (2017).
Hirabayashi, Y. et al. ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons. Science 358, 623–630 (2017).
Lees, J. A. et al. Lipid transport by TMEM24 at ER–plasma membrane contacts regulates pulsatile insulin secretion. Science 355, eaah6171 (2017).
Jeong, H., Park, J., Jun, Y. & Lee, C. Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites. Proc. Natl Acad. Sci. USA 114, E9502–E9511 (2017).
Kawano, S. et al. Structure–function insights into direct lipid transfer between membranes by Mmm1– Mdm12 of ERMES. J. Cell Biol. 217, 959–974 (2017). Structural and biochemical studies show that heterodimers of the ERMES SMP domains from Mdm12 and Mmm1 transfer lipid efficiently both in vivo and in vitro. This finding resolved doubts whether ERMES subunits (and SMP in general) can act as LTPs. These doubtas had arisen because monomeric SMP domains achieved only poor rates of lipid transfer in multiple studies following the original link between SMP and lipid transfer in 2010 (see ref. 55).
Ekiert, D. C. et al. Architectures of lipid transport systems for the bacterial outer membrane. Cell 169, 273–285 (2017). This article presents extensive and compelling electron microscopy structural studies on multimeric MCE domains and supercoiled helical extensions that form macromolecular tubular LTPs.
Awai, K., Xu, C., Tamot, B. & Benning, C. A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking. Proc. Natl Acad. Sci. USA 103, 10817–10822 (2006).
Gatta, A. T. & Levine, T. P. Piecing together the patchwork of contact sites. Trends Cell Biol. 27, 214–229 (2017).
Prinz, W. A. Bridging the gap: membrane contact sites in signaling, metabolism & organelle dynamics. J. Cell Biol. 205, 759–769 (2014).
Gatta, A. T. et al. A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport. eLife 4, e07253 (2015).
Murley, A. et al. Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts. J. Cell Biol. 209, 539–548 (2015).
Loewen, C. J. R., Roy, A. & Levine, T. P. A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J. 22, 2025–2035 (2003). This paper provides the first identification of widespread dual-membrane targeting of LTPs, which targets them to membrane contact sites.
Tong, J., Manik, M. K., Im, Y. J. & Russell, D. W. Structural basis of sterol recognition and nonvesicular transport by lipid transfer proteins anchored at membrane contact sites. Proc. Natl Acad. Sci. USA 115, E856–E865 (2018).
Kumagai, K., Kawano, M., Shinkai-Ouchi, F., Nishijima, M. & Hanada, K. Interorganelle trafficking of ceramide is regulated by phosphorylation- dependent cooperativity between the PH and START domains of CERT. J. Biol. Chem. 282, 17758–17766 (2007).
Kumagai, K., Kawano-Kawada, M. & Hanada, K. Phosphoregulation of the ceramide transport protein CERT at serine 315 in the interaction with VAMP-associated protein (VAP) for inter-organelle trafficking of ceramide in mammalian cells. J. Biol. Chem. 289, 10748–10760 (2014).
Prashek, J. et al. Interaction between the PH and START domains of ceramide transfer protein competes with phosphatidylinositol 4-phosphate binding by the PH domain. J. Biol. Chem. 292, 14217–14228 (2017).
Giordano, F. et al. PI(4,5)P2-dependent and Ca2+-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153, 1494–1509 (2013).
Bian, X., Saheki, Y. & De Camilli, P. Ca2+ releases E-Syt1 autoinhibition to couple ER-plasma membrane tethering with lipid transport. EMBO J. 37, 219–234 (2018).
Saheki, Y. et al. Control of plasma membrane lipid homeostasis by the extended synaptotagmins. Nat. Cell Biol. 18, 504–515 (2016).
Li, X. et al. Analysis of oxysterol binding protein homologue Kes1p function in regulation of Sec14p-dependent protein transport from the yeast Golgi complex. J. Cell Biol. 157, 63–77 (2002).
Mesmin, B. et al. STARD4 abundance regulates sterol transport and sensing. Mol. Biol. Cell 22, 4004–4015 (2011).
Darwiche, R., Mène-Saffrané, L., Gfeller, D., Asojo, O. A. & Schneiter, R. The pathogen-related yeast protein Pry1, a member of the CAP protein superfamily, is a fatty acid-binding protein. J. Biol. Chem. 292, 8304–8314 (2017).
Gamir, J. et al. The sterol-binding activity of PATHOGENESIS-RELATED PROTEIN 1 reveals the mode of action of an antimicrobial protein. Plant J. 89, 502–509 (2017).
Choudhary, V. & Schneiter, R. Pathogen-Related Yeast (PRY) proteins and members of the CAP superfamily are secreted sterol-binding proteins. Proc. Natl Acad. Sci. USA 109, 16882–16887 (2012).
Park, B. S. & Lee, J.-O. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp. Mol. Med. 45, e66 (2013).
Wang, B. et al. Transient production of artemisinin in Nicotiana benthamiana is boosted by a specific lipid transfer protein from A. annua. Metab. Eng. 38, 159–169 (2016).
Leborgne-Castel, N. et al. The plant defense elicitor cryptogein stimulates clathrin-mediated endocytosis correlated with reactive oxygen species production in bright yellow-2 tobacco cells. Plant Physiol. 146, 1255–1266 (2008).
Seutter von Loetzen, C. et al. Ligand recognition of the major birch pollen allergen bet v 1 is isoform dependent. PLOS ONE 10, e0128677 (2015).
Van Winkle, R. C. & Chang, C. The biochemical basis and clinical evidence of food allergy due to lipid transfer proteins: a comprehensive review. Clin. Rev. Allergy Immunol. 46, 211–224 (2014).
Okuda, S., Freinkman, E. & Kahne, D. Cytoplasmic ATP hydrolysis powers transport of lipopolysaccharide across the periplasm in E. coli. Science 338, 1214–1217 (2012).
Simpson, B. W. et al. Identification of residues in the lipopolysaccharide ABC transporter that coordinate ATPase activity with Extractor function. MBio 7, e01729–e01716 (2016).
Okuda, S., Sherman, D. J., Silhavy, T. J., Ruiz, N. & Kahne, D. Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat. Rev. Microbiol. 14, 337–345 (2016).
Phillips, M. C. Is ABCA1 a lipid transfer protein? J. Lipid Res. 59, 749–763 (2018).
Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003).
Friedman, J. R. et al. Lipid homeostasis is maintained by dual targeting of the mitochondrial PE biosynthesis enzyme to the ER. Dev. Cell 44, 261–270 (2017).
Das, A., Brown, M. S., Anderson, D. D., Goldstein, J. L. & Radhakrishnan, A. Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. eLife 3, e02882 (2014).
Lange, Y. & Steck, T. L. Active membrane cholesterol as a physiological effector. Chem. Phys. Lipids 199, 74–93 (2016).
Vienken, H. et al. Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann–Pick disease type C-like phenotype with enhanced lysosomal Ca2+ storage. Sci. Rep. 7, 43575 (2017).
Bigay, J. & Antonny, B. Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity. Dev. Cell 23, 886–895 (2012).
Mesmin, B. et al. Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP. EMBO J. 36, 3156–3174 (2017).
Mesmin, B. et al. 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 (2013).
von Filseck, J. M., Vanni, S., Mesmin, B., Antonny, B. & Drin, G. A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes. Nat. Commun. 6, 6671 (2015).
Zewe, J. P., Wills, R. C., Sangappa, S., Goulden, B. D. & Hammond, G. R. SAC1 degrades its lipid substrate PtdIns4P in the endoplasmic reticulum to maintain a steep chemical gradient with donor membranes. eLife 7, e35588 (2018).
Stoeck, I. K. et al. Hepatitis C virus replication depends on endosomal cholesterol homeostasis. J. Virol. 92, e01196–17 (2017).
Kim, Y. J., Guzman-Hernandez, M. L., Wisniewski, E. & Balla, T. Phosphatidylinositol–phosphatidic acid exchange by Nir2 at ER–PM contact sites maintains phosphoinositide signaling competence. Dev. Cell 33, 549–561 (2015).
Miyata, N., Watanabe, Y., Tamura, Y., Endo, T. & Kuge, O. Phosphatidylserine transport by Ups2–Mdm35 in respiration-active mitochondria. J. Cell Biol. 214, 77–88 (2016).
Ridgway, N. D., Dawson, P. A., Ho, Y. K., Brown, M. S. & Goldstein, J. L. Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding. J. Cell Biol. 116, 307–319 (1992).
Manford, A. G., Stefan, C. J., Yuan, H. L., MacGurn, J. A. & Emr, S. D. ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology. Dev. Cell 23, 1129–1140 (2012).
Sullivan, D. P., Ohvo-Rekilä, H., Baumann, N. A., Beh, C. T. & Menon, A. K. Sterol trafficking between the endoplasmic reticulum and plasma membrane in yeast. Biochem. Soc. Trans. 34, 356–358 (2006).
Iaea, D. B., Mao, S., Lund, F. W. & Maxfield, F. R. Role of STARD4 in sterol transport between the endocytic recycling compartment and the plasma membrane. Mol. Biol. Cell 28, 1111–1122 (2017). This comprehensive in vivo analysis of one major LTP shows that the cholesterol transfer protein STARD4 accounts for ~33% of non-vesicular traffic, which in turn accounts for 75% of the total cholesterol traffic (thus, STARD4 accounts for ~25% of total cholesterol traffic).
Georgiev, A. G. et al. Osh proteins regulate membrane sterol organisation but are not required for sterol movement between the ER and PM. Traffic 12, 1341–1355 (2011).
Ling, Y., Hayano, S. & Novick, P. Osh4p is needed to reduce the level of phosphatidylinositol-4-phosphate on secretory vesicles as they mature. Mol. Biol. Cell 25, 3389–3400 (2014).
Wong, L. H., Čopič, A. & Levine, T. P. Advances on the transfer of lipids by lipid transfer proteins. Trends Biochem. Sci. 42, 516–530 (2017).
Grabon, A. et al. Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. J. Biol. Chem. 292, 14438–14455 (2017). This paper presents an analysis of how PITP might move lipids, including energy state calculation and molecular simulations of the earliest steps of LTP–membrane interaction, showing that lipid ‘jumps’ part way into the LTP within a microsecond but that complete entry into the hydrophobic cavity is unlikely in that timescale.
Wang, P. et al. AAA ATPases regulate membrane association of yeast oxysterol binding proteins and sterol metabolism. EMBO J. 24, 2989–2999 (2005).
Wang, P. Y., Weng, J. & Anderson, R. G. OSBP is a cholesterol-regulated scaffolding protein in control of ERK1/2 activation. Science 307, 1472–1476 (2005).
Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009).
Zhao, K. & Ridgway, N. D. Oxysterol-binding protein-related protein 1L regulates cholesterol egress from the endo-lysosomal system. Cell Rep. 19, 1807–1818 (2017).
Barral, D. C. & Brenner, M. B. CD1 antigen presentation: how it works. Nat. Rev. Immunol. 7, 929–941 (2007).
Zeissig, S. et al. Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. J. Clin. Invest. 120, 2889–2899 (2010).
Sandhoff, K. Neuronal sphingolipidoses: membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism. Biochimie 130, 146–151 (2016).
Wright, C. S., Mi, L.-Z., Lee, S. & Rastinejad, F. Crystal structure analysis of phosphatidylcholine — GM2-activator product complexes: evidence for hydrolase activity. Biochemistry 44, 13510–13521 (2005).
Iyer, L. M., Koonin, E. V. & Aravind, L. Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily. Proteins 43, 134–144 (2001).
Hsu, N. Y. et al. Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell 141, 799–811 (2010).
Albulescu, L. et al. Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP. Antiviral Res. 117, 110–114 (2015).
Shoulders, C. C. et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDA subunit of a microsomal triglyceride transfer protein. Hum. Mol. Genet. 2, 2109–2116 (1993).
Cuchel, M. et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356, 148–156 (2007).
Wang, M. L. et al. Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metab. 12, 166–173 (2010).
Kwon, H. J. et al. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137, 1213–1224 (2009).
Davies, J. P., Chen, F. W. & Ioannou, Y. A. Transmembrane molecular pump activity of Niemann–Pick C1 protein. Science 290, 2295–2298 (2000).
Tomasetto, C. et al. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11–q21.3 region of chromosome 17. Genomics 28, 367–376 (1995).
Wilhelm, L. P. et al. STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. EMBO J. 36, 1412–1433 (2017).
Eden, E. R. et al. Annexin A1 tethers membrane contact sites that mediate ER to endosome cholesterol transport. Dev. Cell 37, 473–483 (2016).
Balboa, E. et al. MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content. Redox Biol. 12, 274–284 (2017).
Kallen, C. B. et al. Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein. J. Biol. Chem. 273, 26285–26288 (1998).
Artemenko, I. P., Zhao, D., Hales, D. B., Hales, K. H. & Jefcoate, C. R. Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. J. Biol. Chem. 276, 46583–46596 (2001).
Kumar, N. et al. VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217, 3625–3639 (2018).VPS13 proteins, found in virtually all eukaryotes, are shown to be LTPs with a completely new fold that transfers multiple phospholipids. The paper also dissects how VPS13A and VPS13C target multiple contact sites. As VPS13 forms a long rod with repeats of the LTP domain, it is strongly predicted to form LTP bridges across contact sites.
AhYoung, A. P. et al. Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly. Proc. Natl Acad. Sci. USA 112, E3179–E3188 (2015).
Acknowledgements
The authors acknowledge funding from the Medical Research Council (grant MR/P010091/1 to L.H.W.), the Wellcome Trust (grant 206346/Z/17/Z to A.T.G.) and the Biotechnology and Biological Sciences Research Council (grant BB/M011801 to T.P.L.).
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Nature Reviews Molecular Cell Biology thanks W. Prinz, F. Maxfield and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Phagophore
-
The double membrane, also termed isolation membrane, that serves as the initiation site for autophagy. Various ATG proteins are recruited to the phagophore to create the autophagosome.
- Lipid desorption
-
The release of a lipid molecule from a membrane bilayer into the aqueous phase. This process requires a high activation energy for highly hydrophobic lipids, such as glycerophospholipids with two acyl chains.
- Oxysterol
-
An oxidized derivative of cholesterol often created by a specific enzyme. Oxysterols are implicated in various cellular processes including cholesterol homeostasis, metabolism and apoptosis.
- Phosphoinositide
-
A PtdIns-based lipid that is further phosphorylated on the inositol head group. Any of the 3, 4 or 5 positions of the sugar ring can be reversibly phosphorylated to make seven different phosphoinositides. Each phosphoinositide has a specific biological activity related to the proteins that interact with it.
- Lipopolysaccharide
-
(LPS). Also known as endotoxin, LPS is a component of the outer membrane of Gram-negative bacteria with structural and protective functions. It is also a strong pro-inflammatory molecule in the immune system of the host.
- Gram-negative bacteria
-
Group of bacteria that do not stain with the crystal violet used in the Gram staining method. They have two membranes, with lipopolysaccharide confined to the outer leaflet of the outer membrane. A peptidoglycan cell wall is found in the periplasmic space between the outer and inner (cytoplasmic) membranes.
- ER–mitochondrial encounter structure
-
(ERMES). A complex of four proteins localized to endoplasmic reticulum–mitochondrial contact sites. The complex arose in the common ancestor of fungi, animals and protists and has since been lost in animals.
- Eugenol
-
A small hydrophobic alkyl benzene component of plant oils that is toxic via effects on cellular membranes.
- Toll-like receptor 4
-
(TLR4). A single-pass transmembrane protein expressed on the surface of sentinel cells of the immune system. TLRs recognize structurally conserved molecules in pathogenic organisms and initiate immune responses via intracellular signalling cascades, often after endocytosis.
- ATP-binding cassette (ABC) transporter
-
A membrane-embedded protein containing an AAA ATPase domain (see below), where consumption of ATP is linked to pumping of a small molecule across the membrane. In ABCA1 and ABCG1, the pumped substrate is a phospholipid, the movement of which leads to cholesterol flux.
- AAA ATPase
-
A protein that couples energy generated by ATP hydrolysis with conformational changes. The variable amino terminus of these proteins is usually involved in substrate recognition. ATP consumption results in energy input into the substrate so that AAA ATPases can act as pumps (see ABC transporters) or as chaperones that change their substrates’ conformation. One chaperone in yeast is Afg2p, which binds Osh1.
- Nuclear steroid receptors
-
Soluble intracellular receptors for steroid hormones (cortisol, oestrogen, etc.) that consist of a steroid-binding domain and a DNA-binding domain. In response to ligand binding, they translocate to the nucleus and regulate transcription.
- γδ T cells
-
T cell subpopulation mostly found in the gut mucosa that expresses a T cell receptor made of one γ and one δ chain (as opposed to the majority of T cells, which express αβ chains). They have a major role in recognizing lipid antigens.
- Abetalipoproteinaemia
-
Human disorder characterized by dysfunctional absorption of dietary fat caused by autosomal recessive mutations in MTTP, impairing the gut’s ability to synthesize chylomicrons and very-low-density lipoprotein from absorbed fat.
- Tangier disease
-
Congenital lack of high-desnity lipoprotein (HDL) through mutation of both genes coding for ABCA1 so that HDL is not formed. Cholesterol builds up as cholesterol ester deposits in otherwise unusual sites, including tonsils, peripheral nerves and the intestine in addition to causing accelerated atherosclerosis.
- Intraluminal vesicle
-
A vesicle generated during endosome maturation by inward budding of the endosomal limiting membrane. When secretory lysosomes fuse with the plasma membrane, intraluminal vesicles are secreted as exosomes.
- Resistance-nodulation-division efflux transporters
-
This large family of permeases (sometimes called pumps, but almost all devoid of ATPase activity) form selective channels for a very wide range of compounds in all kingdoms of life.
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Wong, L.H., Gatta, A.T. & Levine, T.P. Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes. Nat Rev Mol Cell Biol 20, 85–101 (2019). https://doi.org/10.1038/s41580-018-0071-5
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DOI: https://doi.org/10.1038/s41580-018-0071-5
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