Hide-and-seek: Cholesterol masks molecules on cell surfaces

“We knew that glycolipids, which are involved in signaling and cellular recognition, were intriguing molecules,” said Dr. Clifford Lingwood, a study author and Senior Scientist in SickKids’ Molecular Structure and Function Program and a professor in the Department of Laboratory Medicine and Pathobiology at the University of Toronto. “Now we know they can be affected by cholesterol, changing how molecules and cells communicate.” The study was published in the April 3 issue of Nature Chemical Biology.

Lingwood points out that cholesterol acts like a cloaking device for cells, and could potentially slow the spread of infectious disease by stopping molecules involved in diseases , such as cholera or E. coli from binding to cells. “If you can hide the cells by changing the cholesterol, then you can make those cells more resistant to pathogens,” says Lingwood. “It’s a very exciting and broad-ranging application of this work.” Other applications could include locating new targets on cells currently masked by cholesterol, for example cancer cells, for treatment of disease.

The team – including scientists from Canada, Finland, Denmark and Germany – began by identifying cholesterol as a key molecule in regulating the appearance of glycolipids on the surface of a cell. Testing showed that cholesterol could hide membrane molecules and reduce the “visibility” of those molecules to others in the system.

To test whether this would also work in a biological body, the team used red blood cells and verotoxin, a toxin created by E. coli. “When we removed cholesterol from the cell membrane, the verotoxin began to bind to the cell’s surface,” says Lingwood. “Clearly, the cholesterol had been masking the binding agent on the cell, hiding it from the verotoxin.”

Considering situations when cholesterol is naturally removed from cells brought the researchers to the idea of sperm maturation. As sperm travels through a woman’s reproductive system, it matures  by loss of cholesterol and readies itself to bind to the egg for fertilization. “It’s the same concept, perfectly illustrated in the natural system,” says Lingwood. “When the cholesterol is removed from the sperm cell during the maturation process, it reveals the carbohydrate molecules located on the cell’s surface.”  

By finding that a cellular recognition process may be regulated by a simple interaction between cholesterol and glycolipids on a cell’s surface, the team has found a way to control molecular communication at the nanoscale, says Lingwood. “It’s a powerful instrument to add to our cellular toolkit.”

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