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Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites

2018; Elsevier BV; Volume: 59; Issue: 8 Linguagem: Inglês

10.1194/jlr.r085324

1539-7262

Kentaro Hanada,

RNA and protein synthesis mechanisms

The endoplasmic reticulum (ER) is the main center for the synthesis of various lipid types in cells, and newly synthesized lipids are delivered from the ER to other organelles. In the past decade, various lipid transfer proteins (LTPs) have been recognized as mediators of lipid transport from the ER to other organelles; inter-organelle transport occurs at membrane contact sites (MCSs) and in a nonvesicular manner. Although the intermembrane transfer reaction catalyzed by LTPs is an equilibrium reaction, various types of newly synthesized lipids are transported unidirectionally in cells. This review provides a brief history of the inter-organelle trafficking of lipids and summarizes the structural and biochemical characteristics of the ceramide transport protein (CERT) as a typical LTP acting at MCSs. In addition, this review compares several LTP-mediated inter-organelle lipid trafficking systems and proposes that LTPs generate unidirectional fluxes of specific lipids between different organelles by indirect coupling with the metabolic reactions that occur in specific organelles. Moreover, the available data also suggest that the major advantage of LTP-mediated lipid transport at MCSs may be the accuracy of delivery. Finally, how cholesterol is enriched in the plasma membrane is discussed from a thermodynamic perspective. The endoplasmic reticulum (ER) is the main center for the synthesis of various lipid types in cells, and newly synthesized lipids are delivered from the ER to other organelles. In the past decade, various lipid transfer proteins (LTPs) have been recognized as mediators of lipid transport from the ER to other organelles; inter-organelle transport occurs at membrane contact sites (MCSs) and in a nonvesicular manner. Although the intermembrane transfer reaction catalyzed by LTPs is an equilibrium reaction, various types of newly synthesized lipids are transported unidirectionally in cells. This review provides a brief history of the inter-organelle trafficking of lipids and summarizes the structural and biochemical characteristics of the ceramide transport protein (CERT) as a typical LTP acting at MCSs. In addition, this review compares several LTP-mediated inter-organelle lipid trafficking systems and proposes that LTPs generate unidirectional fluxes of specific lipids between different organelles by indirect coupling with the metabolic reactions that occur in specific organelles. Moreover, the available data also suggest that the major advantage of LTP-mediated lipid transport at MCSs may be the accuracy of delivery. Finally, how cholesterol is enriched in the plasma membrane is discussed from a thermodynamic perspective. Erratum: Lipid-transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sitesJournal of Lipid ResearchVol. 59Issue 10PreviewVOL 59 (2018) PAGES 1341–1366 Full-Text PDF Open Access Eukaryotic cells have various membrane-bound distinct compartments, called organelles, with specific functions. Subcellular compartmentalization appears to have been a fundamental event in the evolution of life, enabling the manipulation of numerous metabolic reactions as well as macromolecule functions in the cell. The functions of each organelle may be largely attributable to specific sets of proteins localized there. However, lipids are also the major constituents of all cell membranes and play crucial roles in organelle structure and function (1.van Meer G. Voelker D.R. Feigenson G.W. Membrane lipids: where they are and how they behave.Nat. Rev. Mol. Cell Biol. 2008; 9: 112-124Crossref PubMed Scopus (3529) Google Scholar, 2.Holthuis J.C. Menon A.K. 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USA. 2003; 100: 14713-14718Crossref PubMed Scopus (111) Google Scholar)CRAL-TRIO, cellular retinaldehyde-binding protein and TRIO guanine exchange factor; PITD, PI-transfer domain; GLTD, glycolipid-transfer domain; TGN, trans Golgi network; OM-IM of Mito, from the outer membrane to the inner membrane of mitochondria; NE, nuclear envelope; MLN64, metastatic lymph node 64. "(?)" represents "currently speculative."a The slash represents "co-exchanging" lipid type. Note that GRAMD1b might mediate sterol/PI(4,5)P2 coexchange (145.Horenkamp F.A. Valverde D.P. Nunnari J. Reinisch K.M. Molecular basis for sterol transport by StART-like lipid transfer domains.EMBO J. 2018; 37: e98002Crossref PubMed Scopus (41) Google Scholar).b LTD composed of two different subunits.c Mmm1, Mdm12, Mdm34, and non-SMP protein Mdm10 forms the ERMES complex in yeast. Open table in a new tab CRAL-TRIO, cellular retinaldehyde-binding protein and TRIO guanine exchange factor; PITD, PI-transfer domain; GLTD, glycolipid-transfer domain; TGN, trans Golgi network; OM-IM of Mito, from the outer membrane to the inner membrane of mitochondria; NE, nuclear envelope; MLN64, metastatic lymph node 64. "(?)" represents "currently speculative." LTPs are defined as proteins capable of transferring lipids between different membranes. The inter-membrane lipid-transfer reaction catalyzed by lipid-transfer domains (LTDs) is essentially an equilibrium reaction: when an LTP is added to a system with multiple membranes with different concentrations of a lipid, the LTP catalyzes the inter-membrane transfer of its ligand lipid toward the equilibrium state, in which the concentrations of the lipid in different membranes are equal. Nevertheless, in living cells, various types of newly synthesized lipids appear to be transported unidirectionally. Thus, to achieve the thermodynamic non-equilibrium transport of lipids, additional factors are required. This review provides a brief history of the inter-organelle trafficking of lipids and summarizes the structural and biochemical characteristics of the ceramide transport protein (CERT) as a typical LTP acting at MCSs. In addition, this review compares several LTP-mediated inter-organelle lipid trafficking systems and proposes that LTPs generate unidirectional fluxes of specific lipids between different organelles by indirect coupling with the metabolic reactions that occur in specific organelles. Moreover, the available data also suggest that the major advantage of LTP-mediated lipid transport at MCSs may be the accuracy of delivery. Finally, how cholesterol is enriched in the plasma membrane (PM) is discussed from a thermodynamic perspective. Because a comprehensive description of inter-organelle transport of lipids is beyond the scope of this review, a focus is here placed on inter-organelle translocation of major lipid types in their biosynthesis in mammalian cells. In mammalian cells (as well as other eukaryotic cells), several glycerophospholipid classes are ubiquitous: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin. Except for cardiolipin (which is exclusively localized to mitochondria), the other five classes are widely distributed to most of the organelles, although phospholipid composition deviates depending on the organelle type and the state of cells. PC is the most abundant phospholipid class (∼50% of total phospholipids) in eukaryotes from fungi to humans. The biosynthetic pathways of the major phospholipids in mammalian cells are depicted in Fig. 1B (4.Vance J.E. 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Wistow G. McMaster C.R. Cloning, genomic organization, and characterization of a human cholinephosphotransferase.J. Biol. Chem. 2000; 275: 29808-29815Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 12.Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Crossref PubMed Scopus (153) Google Scholar): CEPT is largely distributed in the ER and nuclear envelope, while CPT is in the Golgi apparatus (12.Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Crossref PubMed Scopus (153) Google Scholar). PC is also synthesized by the methylation of PE in the ER in the liver. PI and PG are synthesized by the CDP-DAG pathway, which differs from the CDP-alcohol pathway (Fig. 1B). The CDP-DAG intermediate is synthesized by the catalytic reaction [phosphatidic acid (PA) + CTP → CDP-DAG + pyrophosphate] of CDP-DAG synthases. There are three isoforms of CDP-DAG synthases in mammalian cells: two isoforms (CDP-DAG synthase 1 and 2) localize to the ER, and one (mammalian homolog of Tam41) localizes to mitochondria (5.Ridgway N.D. Phospholipid synthesis in mammalian cells.Biochemistry of Lipids, Lipoproteins and Membranes. 2016; : 209-236Crossref Scopus (3) Google Scholar, 13.Tamura Y. Harada Y. Nishikawa S. Yamano K. Kamiya M. Shiota T. Kuroda T. Kuge O. Sesaki H. Imai K. et al.Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria.Cell Metab. 2013; 17: 709-718Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). PI is synthesized by PI synthase (CDP-DAG + myo-inositol → PI + CMP) in the ER. After being transported to other organelles, PI is phosphorylated to produce various phosphoinositide species, which often serve as important modulators in the formation and function of organelles (14.De Craene J.O. Bertazzi D.L. Bar S. Friant S. Phosphoinositides, major actors in membrane trafficking and lipid signaling pathways.Int. J. Mol. Sci. 2017; 18: E634Crossref PubMed Scopus (56) Google Scholar, 15.Choy C.H. Han B.K. Botelho R.J. Phosphoinositide diversity, distribution, and effector function: stepping out of the box.BioEssays. 2017; 39Crossref PubMed Scopus (18) Google Scholar). The synthesis of PG and cardiolipin occurs in the inner membrane of mitochondria: PA is transported from the ER to mitochondria (as described in the Other LTP-Mediated Pathways that Act at MCSs section) and is converted to CDP-DAG by Tam41 (13.Tamura Y. Harada Y. Nishikawa S. Yamano K. Kamiya M. Shiota T. Kuroda T. Kuge O. Sesaki H. Imai K. et al.Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria.Cell Metab. 2013; 17: 709-718Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Then, CDP-DAG is converted to PG-1-phosphate (CDP-DAG + glycerol-3-phosphate → PG-1-phosphate + CMP) by its synthase. PG-1-phosphate is dephosphorylated by PG-1-phosphate phosphatase to produce PG, which is converted to cardiolipin (PG + CDG-DAG → cardiolipin + CMP) by cardiolipin synthase. PG is moved from the inner to the outer mitochondrial membrane, and then to the ER, while cardiolipin is restricted to the inner mitochondrial membrane (cardiolipin is exposed to the outer membrane as described below). It remains uncertain whether the CDP-DAG produced by ER enzymes is transported to the inner mitochondrial membrane. In mammalian cells, PS is predominantly synthesized in the ER by the base-exchange reaction of PS synthases using PC (for PS synthase I) and PE (for PS synthase II) as precursors (PC/PE + l-serine → PS + choline/ethanolamine) (Fig. 1B) (16.Kuge O. Nishij