
Lipid traffic: floppy drives and a superhighway
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KEY POINTS * Eukaryotic cells contain hundreds of different lipid species that are distributed unevenly between subcellular organelles and also between the two leaflets of the bilayer of
each organelle. Non-random lipid distributions are maintained despite extensive membrane trafficking between different organelles, and cannot be explained by local metabolism alone. * Lipids
in cells are subject to sorting, and this process probably involves the capacity of lipids to self-organize into phase-separated microdomains. However, a general consensus on the size,
shape and dynamics of such lipid microdomains is lacking at present. * Phospholipids show a fast lateral diffusion in a bilayer, but the rate of their spontaneous flip–flop between the
leaflets is slow. Cells contain flippases that facilitate the energetically unfavourable movement of the phospholipid head group through the hydrophobic membrane interior, and these
activities are increasingly being attributed to specific proteins. * Flippases have a key role in membrane stability, as well as in the mechanism by which cells avoid being killed by
macrophages. By expanding one membrane leaflet at the expense of the other, unidirectional flippases might participate in membrane folding and vesiculation. * The trafficking of particular
lipids between organelles is mediated by lipid-transfer proteins that shuttle across cytosolic gaps. For them to function efficiently, these proteins must target both donor and acceptor
membranes, and the proteins that have been identified as having such a dual-membrane-targeting ability are found at sites where the two membranes are in close proximity. * Flippases and
lipid-transfer proteins both move lipids over short distances (approximately 10 nm), whereas other mechanisms — such as vesicular trafficking and diffusion within individual pan-cellular
organelles (in particular, the endoplasmic reticulum) — can move lipids across the whole cell. ABSTRACT Understanding how membrane lipids achieve their non-random distribution in cells is a
key challenge in cell biology at present. In addition to being sorted into vesicles that can cross distances of up to one metre, there are other mechanisms that mediate the transport of
lipids within a range of a few nanometres. These include transbilayer flip–flop mechanisms and transfer across narrow gaps between the endoplasmic reticulum and other organelles, with the
endoplasmic reticulum functioning as a superhighway along which lipids can rapidly diffuse. Access through your institution Buy or subscribe This is a preview of subscription content, access
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Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A DYNAMIC PARTITIONING MECHANISM POLARIZES MEMBRANE PROTEIN
DISTRIBUTION Article Open access 30 November 2023 STRUCTURAL AND FUNCTIONAL CONSEQUENCES OF REVERSIBLE LIPID ASYMMETRY IN LIVING MEMBRANES Article 16 November 2020 REGULATION OF MEMBRANE
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Google Scholar Download references ACKNOWLEDGEMENTS We apologize for the omission of many significant papers that could not be cited or discussed due to space limitations. Work in the
authors' laboratories is funded by grants from the Utrecht University High Potential Programme and the Netherlands Organization for Scientific Research (J.C.M.H.), and from The Wellcome
Trust, the Biotechnology and Biological Sciences Research Council, and Fight For Sight (T.P.L.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Membrane Enzymology, Institute
of Biomembranes, Utrecht University, Padualaan 8, Utrecht, 3584 CH, The Netherlands Joost C. M. Holthuis * Department of Cell Biology, Institute of Ophthalmology, 11–43 Bath Street, London,
EC1V 9EL, UK Tim P. Levine Authors * Joost C. M. Holthuis View author publications You can also search for this author inPubMed Google Scholar * Tim P. Levine View author publications You
can also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY
INFORMATION S1 (PDF 29 KB) SUPPLEMENTARY INFORMATION S2 (PDF 30 KB) RELATED LINKS RELATED LINKS DATABASES FLYBASE Rdgbα INTERPRO PH domain StART domain SACCHAROMYCES GENOME DATABASE Osh1
Osh2 Osh3 Psd2 Rsb1 Rft1 Sec14 Sfh4 SWISS-PROT ABCA1 ABCA4 ABCB1 ABCB4 ABCD1 ABCG5 ABCG8 CERT MLN64 ORP5 ORP8 OSBP PLSCR1 VAP GLOSSARY * WOBBLE Movement in which the lipid molecule partially
dips into the opposite leaflet of the bilayer and then moves back to its original position without changing its longitudinal orientation. * PHOSPHOINOSITIDE A phosphorylated derivative of
the glycerolipid phosphatidylinositol. As three positions of the inositol ring can be phosphorylated independently of each other, there are seven possible phosphoinositides. * BIOGENIC
MEMBRANE A membrane that can synthesize lipids. Biogenenic membranes include the plasma membrane in Gram-positive bacteria, the inner membrane in Gram-negative bacteria and the endoplasmic
reticulum in eukaryotes. * FLIPPASE A general term that refers to a protein, or protein complex, that facilitates the energetically unfavourable movement of the polar head group of a
phospholipid or glycosphingolipid through the hydrophobic interior of a membrane. * TRANSLOCASE A lipid translocase is a flippase that uses ATP hydrolysis to catalyse the unidirectional
movement of a lipid from one membrane leaflet to the other. Translocases help to create asymmetric lipid distributions across the bilayer. A well-known example is the aminophopsholipid
translocase that is responsible for the selective sequestration of phosphatidylserine and phosphatidylethanolamine in the cytosolic leaflet of the plasma membrane. * EXOPLASMIC LEAFLET The
non-cytosolic leaflet of a membrane, which faces the extracellular space or the lumen of an organelle. * SCRAMBLASE An energy-independent, bidirectional lipid flippase that, when activated
by a transient rise in intracellular Ca2+ levels, disrupts lipid asymmetry by facilitating a rapid equilibration of lipids between the two membrane leaflets. * EXOCYTIC PATHWAY Newly
synthesized proteins that are destined for the cell surface are first imported by the endoplasmic reticulum, then move through the Golgi complex and, finally, are packaged into secretory
vesicles that fuse with the plasma membrane. * _TRANS_-GOLGI The Golgi apparatus is composed of a stack of flattened cisternae (bags), which is asymmetric. Post-endoplasmic-reticulum
carriers fuse together to make the _cis_ side of the Golgi, whereas the _trans_ side is where post-Golgi carriers form. * ANTEROGRADE/RETROGRADE Terms that signify the direction in which
vesicles move. Cargo that is destined for the cell surface moves in the anterograde direction, and movement in the opposite direction, namely from the cell surface toward the endoplasmic
reticulum, is retrograde. * COPI-COATED VESICLES Transport vesicles that bud from the Golgi due to the assembly of a cytosolic coat protein known as coatomer protein (COP)I. * LIPID
MICRODOMAINS Lateral lipid assemblies that form spontaneously in the bilayer due to a differential miscibility of membrane lipids. Microdomains are typically enriched in sphingolipids and
sterols, and have been postulated to acquire specific functions by concentrating or excluding specific membrane proteins. Conversely, membrane proteins might affect microdomain size,
composition and lifespan. * APICAL MEMBRANE The region of the plasma membrane of an epithelial cell that faces the lumen. The region that is connected to the underlying tissue is known as
the basolateral membrane. * GPI-ANCHORED PROTEINS Proteins that are primarily found at the cell surface and that are attached to the bilayer by means of a lipid anchor, which is composed of
glycosylphosphatidylinositol (GPI). * P-TYPE ATPASES A ubiquitous family of polytopic membrane proteins that use the energy of ATP to transport ions across cellular membranes against a
concentration gradient. A distinctive biochemical feature of these pumps is an acid-stable phosphorylated aspartate residue that forms during the pumping cycle, and the phosphorylated (P)
intermediate gives the family its name. * FAMILIAL INTRAHEPATIC CHOLESTASIS A rare inherited condition in children, in which patients are unable to secrete bile from the liver, which often
progresses to an irreversible scarring of the liver (cirrhosis) within the first decade of life. * ANGELMAN SYNDROME A neurological disorder, also named 'happy puppet' syndrome, in
which severe learning difficulties are associated with a characteristic facial appearance and behaviour. * OUTER-SEGMENT DISC MEMBRANE The outer segment of rod cells contains a stack of
discs, which are each formed by a closed membrane in which the photoreceptor rhodopsin is embedded. * APOLIPOPROTEINS Proteins that form scaffolds for extracellular lipoprotein particles
that carry lipids (triglycerides and cholesterol esters) between the liver and peripheral tissues. * TANGIER DISEASE A genetic disorder that is characterized by a defect in the efflux of
cholesterol and its associated esters to high-density lipoproteins. The disease was first identified in a five-year-old inhabitant of the island of Tangier, located off the coast of
Virginia, USA. * ADRENOLEUKODYSTROPHY An inherited metabolic disorder in which the myelin sheath on nerve fibres is lost and the adrenal gland degenerates, which leads to progressive
neurological disability and death. People with adrenoleukodystrophy accumulate high levels of very-long-chain fatty acids in their brain and adrenal cortex, because the fatty acids are not
broken down in a normal manner. * PERIPHERAL MEMBRANE PROTEINS Proteins that have an affinity for a membrane because they bind to a membrane receptor (either another membrane protein or a
lipid head group). They do not integrate into the hydrophobic core of the bilayer. * PARASITOPHOROUS VACUOLE A membrane-bound organelle that contains an intracellular parasite, such as
_Toxoplasma gondii_. Although the membrane that surrounds this organelle is derived from the host, it is modified by the parasite to facilitate its survival and growth. * INTEGRAL MEMBRANE
PROTEIN A protein with a moiety (either a covalently linked lipid or a transmembrane domain) that is integrated into the hydrophobic core of the bilayer. * AVIDITY The overall measure of
binding between a multivalent ligand and its receptors. It was originally defined for antibodies, for which avidity refers to the overall strength of binding between multivalent antigens and
antibodies. * GOLGI–ER–LYSOSOME (GERL). This term, which has fallen into disuse, was used by Alex Novikoff to describe what is, at present, called the _trans_-endoplasmic reticulum (ER) —
that is, flattened ER cisternae that are intercalated between cisternae of the _trans_-Golgi. Claims of direct membrane continuity between GERL and adjacent lysosomes have not been
substantiated. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Holthuis, J., Levine, T. Lipid traffic: floppy drives and a superhighway. _Nat Rev Mol
Cell Biol_ 6, 209–220 (2005). https://doi.org/10.1038/nrm1591 Download citation * Issue Date: 01 March 2005 * DOI: https://doi.org/10.1038/nrm1591 SHARE THIS ARTICLE Anyone you share the
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