Cell biology

Countercurrents in lipid flow

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Two studies find that a lipid-exchange cycle mediates the enrichment of the lipid phosphatidylserine in the cell membrane compared with the membrane of an organelle called the endoplasmic reticulum, where the lipid is produced.

How lipids reach their destinations inside a cell is largely unknown. Most are synthesized in an organelle called the endoplasmic reticulum (ER) and must be delivered to other parts of the cell with speed and specificity. For example, the lipid phosphatidylserine is enriched on the inner surface of the plasma membrane. How does it get there from the ER, and how does it become enriched at the plasma membrane? Two papers in Science1,2 now present a single mechanism that resolves both of these problems.

The membranes that encase the cell and its various organelles each have a unique composition of proteins and lipids. In most instances, proteins are delivered to these membranes by vesicle shuttles that originate in the ER. But many lipids favour non-vesicular modes of transport3. These are faster than vesicular trafficking4 and can produce considerable asymmetries in the lipid compositions of different membranes, leading to lipid enrichment at the plasma membrane compared with the ER.

Because lipids are insoluble in water4, during non-vesicular transport they must be shielded from the water-rich cytoplasm by proteins that can hold them in an internal pocket. Such lipid-transfer proteins (LTPs) often act in regions in which the ER comes to within 30 nanometres of another membrane4,5. One class of LTP known to mediate ER–membrane contacts is the family related to oxysterol-binding protein (OSBP), which was originally shown6 to bind sterols such as oxygenated cholesterol derivatives. Members of this family, named OSBP-related proteins (ORPs) in mammalian cells and OSBP homologues (Osh proteins) in yeast, are characterized by their OSBP-related lipid-binding domain (ORD).

Osh6 and Osh7 in yeast make complexes with phosphatidylserine rather than sterol7, indicating that, despite the family name, not all ORD-containing proteins are sterol binders. It is also known that ORD-containing proteins can bind to two different lipids, even though LTPs generally show specificity for one lipid only. The only amino-acid residues that are evolutionarily conserved in all ORD-containing proteins bind to the lipid phosphatidylinositol-4-phosphate (PI4P), rather than to phosphatidylserine or sterol8,9. Furthermore, although there are two lipid-binding sites inside the pocket of ORD-containing proteins, the sites overlap considerably, meaning that there is room for only one lipid at a time.

In vitro, LTPs can facilitate lipid diffusion only down concentration gradients, which in vivo would lead to equal concentrations of any given lipid at each membrane. Could the bispecificity of ORD-containing proteins help them to establish asymmetric lipid concentrations? Previous research8,10 suggests that Osh4 and OSBP mediate the transport of cholesterol from the ER to another organelle, the Golgi, by balancing cholesterol transport in one direction with PI4P transport in the other. PI4P is synthesized in the plasma membrane, Golgi and vesicles called endosomes11, and is hydrolysed to phosphatidylinositol by a PI4P phosphatase enzyme called Sac1 that resides in the ER. The lack of PI4P in the ER membrane ensures that Osh4 and OSBP can bind only cholesterol at the ER. On arrival at the Golgi, Osh4 and OSBP offload cholesterol in exchange for more PI4P, allowing the cycle to continue. In this way, even though both cholesterol and PI4P are found at lower levels in the ER than in the Golgi, cholesterol can become enriched in the Golgi12.

Could a PI4P countercurrent also drive traffic of phosphatidylserine to the plasma membrane? In one of the new studies, Moser von Filseck et al. resolved the structure of the Osh6–PI4P complex (the structure of the Osh6–phosphatidylserine complex is already known7), and showed that Osh6 can exchange phosphatidylserine for PI4P between vesicle populations in vitro. The ORDs of ORP5 and ORP8 are the closest mammalian counterparts to those of Osh6 and Osh7, and, in the other study, Chung et al. showed that the ORD of ORP8 contained phosphatidylserine or PI4P when purified from cells.

Both groups showed that the LTPs were concentrated at contact sites between the ER and the plasma membrane. It is unclear how Osh6 and Osh7 achieve this, but Chung and colleagues found that ORP5 and ORP8 bind to receptors on both membranes. Both studies then showed that these proteins transfer phosphatidylserine from the ER to the plasma membrane, where the proteins pick up PI4P that is subsequently delivered to Sac1. This cycle enriches phosphatidylserine at the plasma membrane (Fig. 1). The hydrolysis of PI4P is a crucial ingredient of this mechanism — the LTPs mediated phosphatidylserine traffic only if they were capable of binding PI4P too, and, in yeast, Sac1 activity was required for phosphatidylserine traffic.

Figure 1: Cycling lipid transport.

Two studies1,2 describe how members of the OSBP protein family move the lipid phosphatidylserine (PS) from its site of synthesis in a cellular organelle called the endoplasmic reticulum (ER) to the inner surface of the plasma membrane, where it becomes enriched. The OSBP-related protein (ORP5 or ORP8 in mammals, Osh6 or Osh7 in yeast) binds PS and another lipid, phosphatidylinositol-4-phosphate (PI4P), in a mutually exclusive fashion. a, PS is picked up at the ER and offloaded at the plasma membrane, in exchange for PI4P. b, PI4P is delivered to the ER, where the phosphatase enzyme Sac1 hydrolyses it to phosphatidylinositol (PI). The cycle is maintained through the continual resynthesis of PI4P from PI at the plasma membrane.

These results will undoubtedly inspire the search for other non-PI4P ligands of proteins related to OSBP, possibly shedding light on the asymmetric transport of many different lipids. Although this is an exciting prospect, the papers raise several questions. First, does Sac1 work exactly as described? Although both papers propose that Sac1 acts after delivery of PI4P to the ER, other evidence13 suggests that it acts on PI4P at the plasma membrane.

Second, is a PI4P countercurrent the only way to transport and enrich lipids at the plasma membrane, Golgi and endosomes? Probably not. Cholesterol and phosphatidylserine might be transported by other means4, becoming enriched in the plasma membrane through a trapping mechanism. Indeed, the possibility that more than one mechanism might perform this task is supported by the fact that yeast cells lacking Osh6 and Osh7 show no defects14. Perhaps the otherwise minor contribution of vesicular transport is increased in these mutants. This could be tested by disabling secretory transport in cells lacking Osh6 and Osh7 or ORP5 and ORP8.

Most data on LTPs have been gathered from in vitro experiments, and so the in vivo role of these proteins remains enigmatic. Until techniques are developed to determine whether the vast bulk of trafficked lipid molecules are solubilized by an LTP, it remains possible that in vitro lipid transfer by LTPs is not matched by the same activity in cells. Instead, LTPs may merely sense lipids, binding them when they are abundant to activate downstream targets that then mediate traffic13. Nonetheless, the fact that identically arranged countercurrents pervade not only the ORD-containing family1,2,8,10,12 but also the Sec14 LTP family15 is strong evidence that some LTPs can transfer lipids in bulk. Footnote 1


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Correspondence to Anant K. Menon or Tim P. Levine.

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Menon, A., Levine, T. Countercurrents in lipid flow. Nature 525, 191–192 (2015) doi:10.1038/525191a

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