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Non-vesicular lipid transport by lipid-transfer proteins and beyond

Key Points

  • Non-vesicular lipid transport plays a crucial part in intracellular lipid trafficking and can be mediated by spontaneous lipid transport or by lipid-transfer proteins (LTPs).

  • LTPs markedly facilitate (by several orders of magnitude) the transport of lipids between membranes in vitro.

  • Non-vesicular lipid transport is thought to be greatly enhanced at membrane contact sites; small cytosolic gaps between the endoplasmic reticulum membrane and virtually all other cellular organelles.

  • LTPs do not mediate a simple vectorial lipid transport from one membrane to another. Rather, they facilitate lipid transport between membranes according to their membrane environment.

  • LTPs use their lipid-transfer activity to regulate various cellular processes, including vesicular trafficking, signal transduction and lipid metabolism.

Abstract

The movement of lipids within and between intracellular membranes is mediated by different lipid transport mechanisms and is crucial for maintaining the identities of different cellular organelles. Non-vesicular lipid transport has a crucial role in intracellular lipid trafficking and distribution, but its underlying mechanisms remain unclear. Lipid-transfer proteins (LTPs), which regulate diverse lipid-mediated cellular processes and accelerate vectorial transport of lipid monomers between membranes in vitro, could potentially mediate non-vesicular intracellular lipid trafficking. Understanding the mechanisms by which lipids are transported and distributed between cellular membranes, and elucidating the role of LTPs in intracellular lipid transport and homeostasis, are currently subjects of intensive study.

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Figure 1: Modes of non-vesicular lipid transport.
Figure 2: Spontaneous lipid exchange between membranes.
Figure 3: Domain organization and three-dimensional structure of LTPs.
Figure 4: Lipid transport at ER-mitochondrion MCSs.
Figure 5: Networking of coordinated functions of LTPs in the Golgi complex of mammalian cells.

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Acknowledgements

Sima Lev is the incumbent of the Joyce and Ben B. Eisenberg Chair of Molecular Biology and Cancer Research. This work was supported by the Israel Science Foundation, Grant number 548/08. The author thanks R. Sertchook from the Weizmann Institute of Science for assistance in collecting the three-dimensional images, A. Menon and O. Laufman for productive discussion, and especially W. Prinz for the critical reading of this manuscript and his intellectual contribution.

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Supplementary information

Supplementary Information S1 (Table)

Apparent half-time (h) for [3H]POPC (1-palmitoyl-2-oleoyl PC) transfer at 37 °C as a function of donor concentration for the indicated acceptor concentrations. (PDF 148 kb)

Supplementary Information S2 (Box)

Measurement of Lipid Transfer Activity in vitro (PDF 234 kb)

Supplementary Information S3 (Figure)

Structure of selected sterols and PtdCho species (PDF 97 kb)

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Glossary

Vesicular transport

An active process in which materials move into or out of the cell enclosed in vesicles. This process is mediated by a sequence of events involving the budding of the vesicles from a donor membrane and their subsequent fusion with an acceptor membrane.

Peroxisome

An organelle present in most eukaryotic cells that is involved in the oxidation of fatty acids and the production and destruction of hydrogen peroxide.

Lipid desorption

The release of a lipid molecule from a lipid bilayer to the surrounding aqueous phase. This process involves both the disruption of lipid–lipid interactions in the bilayer and the formation of a cavity in the aqueous phase that accommodates the diffusing lipid molecule.

Vectorial lipid transport

A directional transport of lipids that is driven by a concentration gradient.

Lipid droplet

An organelle that stores neutral lipids and has a crucial role in lipid metabolism.

Flippase

A membrane protein that catalyses the transport of lipids across the membrane bilayer in an ATP-dependent manner. Flippases commonly transport lipids towards the cytoplasm, whereas floppases transport lipids from the cytofacial surface to the opposite side of the membrane.

Membrane curvature

The bending of the membrane, which can be influenced by the relative distribution of cone-like and inverted cone-like lipids (for example, diacylglcerol and phosphatidic acid, and lysophospholipids, respectively) between the inner or outer leaflets of the bilayer.

Vesicle fission

The pinching-off of a vesicle from a membrane bilayer.

Vesicle fusion

The merging of a vesicle with a membrane bilayer.

Condensed complex

A complex formed between cholesterol and saturated phospholipids with long fatty acid chains or with sphingomyelin.

First-order process

A reaction with a rate that is proportional to the concentration of only one reactant. Other reactants can be present but have no influence on the reaction rate.

Second-order process

A reaction with a rate that is proportional to the square concentration of a single reactant or to the concentration of two reactants.

Thermal motion

The random motion of lipid molecules in the bilayer that is due to temperature.

Hydration force

The repulsive force acting between apposing lipid bilayers in aqueous solution.

Liposome

An artificial microscopic vesicle consisting of an aqueous core surrounded by a lipid bilayer.

Membrane fluidity

The viscosity of the lipid bilayer, which is determined by the length and saturation of the fatty-acid side chains of phospholipids and the content of cholesterol and sphingolipids..

Phosphoinositide

The phosphorylated form of PtdIns. The inositol ring of PtdIns can be phosphorylated in three different positions (3, 4 and 5), yielding seven distinct phosphoinositides. Phosphoinositides play a key part in signal transduction and membrane trafficking.

PH domain

A protein domain of 100 amino acids that is present in numerous proteins and in many cases binds phosphoinositides with high affinity and specificity.

FFAT motif

A short sequence motif, containing the EFFDAxE consensus sequence, that has been identified in 17 eukaryotic proteins, most of which are involved in lipid transfer, sensing or binding.

PtdIns-transfer domain

A protein domain that is present in PITPs and mediates the exchange of PtdIns for PtdCho, and vice versa. PITPs have a 16-fold higher binding affinity for PtdIns than PtdCho.

Steroidogenesis

The biosynthesis of steroid hormones.

AP1 complex

A heterotetrameric complex with a role in protein sorting at the trans-Golgi network and endosomes. AP1 mediates the recruitment of clathrin to membranes and the recognition of sorting signals in the cytosolic tails of transmembrane cargo proteins.

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Lev, S. Non-vesicular lipid transport by lipid-transfer proteins and beyond. Nat Rev Mol Cell Biol 11, 739–750 (2010). https://doi.org/10.1038/nrm2971

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