Researchers in the United States have discovered a new class of biomolecules – called glycoRNA – on cell surfaces in a number of animals, including humans. The finding comes as a complete surprise to scientists who aren’t sure what these molecules actually do in the body, but they could play a previously unexplored role in health and disease.

Sugars, called glycans, are central to all life. They normally exist outside of cells or on cell surfaces and regulate many cellular functions, including embryonic development and host-pathogen recognition. They do this by attaching themselves to proteins and lipids and modifying them through a process called glycosylation. Proteins and lipids are abundant on cell surfaces and no other biomolecule has previously been considered a target for glycosylation. But now it turns out that glycans also interact with RNA. It is particularly surprising because RNA has been linked to processes in cells.

Ryan Flynn in Carolyn Bertozzi’s laboratory at Stanford University made the discovery while studying the potential of an enzyme to glycosylate RNA. For two decades, Bertozzi has pioneered bioorthogonal chemistry, which enables glycans and their interactions with proteins and lipids to be studied in real time in living systems without disrupting biological processes.

A picture with small RNAs

“The beauty of this chemistry is that it is flexible for each experiment to which it is applied,” says Bertozzi. “When Ryan asked about RNA on glycans, he was able to use this bioorthogonal chemistry technology to see if glycans were attached to RNAs, and they were.”

Flynn’s main experiment revolved around the enzyme glycosyltransferase and RNA, but they did not observe glycosylation. However, a control experiment inadvertently delivered the goods. The control had used cells labeled with a reporter molecule. It was a control because that label tracks glycans where RNA is normally not found, especially in the Golgi apparatus where proteins and lipids are packaged before they are sent out of the cell. However, the reporter molecule gave strong signals that indicate RNA glycosylation. Further experiments with human, mouse, hamster and zebrafish cells confirmed the presence of glycoRNA, suggesting that the biomolecule is common in life.

“It was both unexpected and exciting,” says Flynn, who is now at Harvard University. ‘That immediately led to a multitude of new questions.’ Since glycoproteins and glycolipids play a role in a number of biological processes in animal, plant and microbial cells, the researchers suspect that glykoRNA has a similarly important function.

“With the data available to us, we are currently examining its role in cell surface biology such as cell-to-cell communication and possibly in the interaction with regulatory receptors in the immune system, the so-called Siglec proteins.” [associated with the autoimmune disease lupus] “Explains Bertozzi.

“The results are amazing and fascinating,” comments Laura Kiessling, who studies cellular carbohydrate chemistry at the Massachusetts Institute of Technology, USA. ‘Specially, No-Glycosylation occurs in the endoplasmic reticulum and then in the Golgi. Given the location and process, it is completely unclear how RNA could be glycosylated in this way.

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