Lipid traffic: floppy drives and a superhighway

• Published in: Nature reviews. Molecular cell biology Vol. 6; no. 3; pp. 209 - 220
• Main Authors: Holthuis, Joost C. M., Levine, Tim P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2005; Nature Publishing Group
• Subjects: Biochemistry; Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Endocytosis - physiology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Exocytosis - physiology; Gram-positive bacteria; Life Sciences; Lipid Bilayers - metabolism; Lipids; Membrane Lipids - metabolism; Membrane Proteins - metabolism; Membranes; Physiology; Plasma; Protein Transport - physiology; Proteins; review-article; Saccharomyces cerevisiae - physiology; Stem Cells
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm1591

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. 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.