The role of cholesterol in membrane fusion

doi:10.1016/j.chemphyslip.2016.05.003

Chemistry and Physics of Lipids

Volume 199, September 2016, Pages 136-143

https://doi.org/10.1016/j.chemphyslip.2016.05.003 Get rights and content

Highlights

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Cholesterol is essential for fusion of secretory vesicles and some enveloped viruses with cell membranes.
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Cholesterol alters the distribution of SNARE and viral fusion proteins in membranes.
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Cholesterol changes the penetration of fusion peptides in membranes.
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Cholesterol alters the intrinsic membrane curvature and bending in membrane fusion.
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Cholesterol alters the lifetime of hemifusion intermediates in membrane fusion.

Abstract

Cholesterol modulates the bilayer structure of biological membranes in multiple ways. It changes the fluidity, thickness, compressibility, water penetration and intrinsic curvature of lipid bilayers. In multi-component lipid mixtures, cholesterol induces phase separations, partitions selectively between different coexisting lipid phases, and causes integral membrane proteins to respond by changing conformation or redistribution in the membrane. But, which of these often overlapping properties are important for membrane fusion?—Here we review a range of recent experiments that elucidate the multiple roles that cholesterol plays in SNARE-mediated and viral envelope glycoprotein-mediated membrane fusion.

Graphical abstract

Introduction

Cholesterol is an essential component of mammalian cells. It is synthesized in a complex series of enzymatic steps in the endoplasmic reticulum and is eventually transported through the Golgi to the plasma membrane where its concentration is much higher than in other cellular compartments. Large reservoirs of cholesterol also reside in blood serum in the form of lipoproteins, which are taken up by cells through endocytosis and recycled into the intracellular pool of cholesterol. Thus cholesterol cycles within cells and in and out of cells with many of these transport functions involving fission and fusion between different membranes. Because cholesterol has profound physical effects on the membranes in which it resides, it is not surprising that membrane cholesterol also dramatically affects membrane fusion and membrane fission. In this review, we first recapitulate briefly some of the unique effects that cholesterol imparts on the host lipid bilayer and some common modes of how cholesterol interacts with integral membrane proteins. This sets the stage to discuss a host of relatively recent discoveries on how cholesterol influences membrane fusion in intracellular membrane traffic, particularly in exocytosis of secretory vesicles, and in cell entry of enveloped viruses whose membranes typically are also highly enriched in cholesterol.

Section snippets

Cholesterol orders lipids and induces phase separation and curvature changes in fluid lipid bilayers

Cholesterol has a unique structure of four fused hydrocarbon rings with a polar hydroxyl group at one end and an eight-carbon branched aliphatic tail at the other end. The ring structure is rigid with an almost flat front face and a more corrugated back face, whereas the tail is flexible and able to undergo trans-gauche isomerizations like the hydrophobic tails of the phospholipids of the bilayer in which cholesterol resides. The small hydroxyl group is the only polar group in the molecule; the

Cholesterol modulates the structure and activity of integral membrane proteins by different mechanisms

Cholesterol influences the behavior of membrane proteins in lipid bilayers in multiple ways (Epand, 2008). Generally, we can distinguish between (i) global effects of the perturbed lipid bilayer, discussed in the previous section, on membrane protein behavior and (ii) specific effects of cholesterol binding to defined binding motifs on membrane proteins. The increased order of the lipid acyl chains results in a reduction of free volume in bilayers when cholesterol is introduced (Falck et al.,

Effect of cholesterol on SNARE-mediated intracellular membrane fusion

Regulated exocytosis is a fundamental biological process where secretory vesicles release cargo products (neurotransmitters, peptides, hormones etc.) into the extracellular space by a process during which the vesicle membrane fuses with the plasma membrane (Rothman, 2014). SNARE (Soluble NSF Attachment Protein Receptor) proteins are at the core of a molecular machinery that leads to pore opening and secretory content release (Tamm et al., 2003, Rothman, 2014). The membrane composition of

Effect of cholesterol on membrane fusion in enveloped virus entry

Membrane fusion is a key step of enveloped virus entry into host cells (Zimmerberg et al., 1993, Blumenthal et al., 2003, Harrison, 2008). While viral surface glycoproteins drive membrane fusion, lipids including cholesterol play critical roles in the fusion process (Chernomordik and Kozlov, 2003, Tamm et al., 2003, Lai et al., 2005) (Fig. 2). A growing body of evidence supports the idea that cholesterol-rich regions serve as platforms for the entry of many enveloped viruses (Manes et al., 2003

Conclusions and future perspectives

Despite extensive research on membrane fusion and an exhaustive literature on the effect of cholesterol on membrane structure and dynamics and on the response of numerous membrane proteins to membrane cholesterol, the intersection of fusion and cholesterol research is surprisingly small. The reasons for this are most likely (i) that many laboratories that study membrane fusion, in the SNARE and viral fusion field, focus on what the respective fusion proteins do, how they interact, and how they

Acknowledgements

This work was supported by NIH grants P01 GM72694 and R01 AI30557 and research program grant RGP0055/2015 from the Human Frontier Science Program. We apologize to all those authors whose work could not be discussed owing to space limitations.

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