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Lipid traffic: floppy drives and a superhighway

Nature Reviews Molecular Cell Biology volume 6, pages 209–220 (2005)Cite this article

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.

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Figure 1: Membrane-lipid distributions.
Figure 2: Mechanisms of lipid transport.
Figure 3: Interbilayer and transbilayer lipid movement.
Figure 4: Models for the coupled sorting of lipids and proteins in the Golgi.
Figure 5: Lipid traffic at membrane contact sites.

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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.).

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  1. Department of Membrane Enzymology, Institute of Biomembranes, Utrecht University, Padualaan 8, Utrecht, 3584 CH, The Netherlands

    Joost C. M. Holthuis

  2. Department of Cell Biology, Institute of Ophthalmology, 11–43 Bath Street, London, EC1V 9EL, UK

    Tim P. Levine

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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.

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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

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