In a surprise find, scientists have discovered sugar-coated RNA molecules decorating the surface of cells.

These so-called “glycoRNAs” poke out from mammalian cells’ outer membrane, where they can interact with other molecules. This discovery, reported in the journal Cell, upends the current understanding of how the cell handles RNAs and glycans.

“This was probably the biggest scientific shock of my life,” says study senior author. “Based on the framework by which we understand cell biology, there’s no place where glycan sugars and RNA would physically touch each other.”

Normally, RNA is made in the nucleus and transported to the cytoplasm, where it serves as a template for making proteins. Until now, scientists thought glycans were kept separate. But the new work suggests that the two molecules actually meet up, and the sugar-coated RNAs take a trip to the cell surface.

The team’s initial findings drew considerable attention when posted them on the preprint server bioRxiv.org in 2019. Now, the scientists report a new physical position for the glycoRNAs, opening a possible role for the sugar-coated RNAs in immune disease.

Researchers have been studying “glycobiology” for decades. Sugars serve a key role in cellular communication, among other functions. Previously, scientists had found glycans attached to proteins and fats. Glycomolecules even stud the cell walls of bacteria and fungi, helping cells communicate and infect their hosts.

Until now, glycobiology and RNA biology did not overlap. Scientists in the two fields use different chemistry and techniques to study their molecules.

The team knew, for instance, of a glycan enzyme that could bind RNAs. That made them wonder if RNA itself could connect with the sugars. And although most glycans reside in a cellular compartment called the Golgi, one type of glycan does mingle in the cytoplasm, where RNA typically dwells.

So they went hunting for glycoRNAs and chemically tagged glycans within the cell and then looked for RNAs among the tagged molecules. A hit would mean they found a molecule that contained both RNA and a sugar. They ran experiments for months. In all that time they couldn’t find anything. But that wasn’t quite true.

They had also been looking for glycoRNAs in the Golgi. Because RNA was not expected to be there, the test served as a negative control – a way to confirm that his experiment was not detecting RNAs everywhere they looked.

But the negative control kept coming back positive. Somehow, RNAs were hooking up with sugars in the Golgi. The team thought the experiment must have been contaminated, the senior author says. “We were trying to come up with a million answers as to how this sugar would be physically associated with RNA.”

They did every experiment they could think of to rule out the possibility that the signal was coming from something besides RNA. The answer never changed. They found the glycoRNAs in every type of cell he could grow in the lab. They even found them in tissues from mice, and, more recently, discovered glycoRNAs on the cell surface.

“They applied every possible way one can imagine to confirm the presence of glycan-modified RNA,” says chemical biologist  who was not involved with the new work.

Meanwhile, researchers in the lab had also been studying a type of cell surface protein called “Siglecs.” These molecules bind to glycans and play a role in the immune system. They wondered if Siglecs could also bind to the newly discovered glycoRNAs.

“This was one of those, ‘let’s just give it a try, who knows’ experiments,” the senior author says. They tested 12 different Siglec molecules and found that two of them stuck to glycoRNAs.

A literature search revealed that one of the Siglec molecules had been previously linked to the autoimmune disease lupus. Finding connections between these different kinds of molecules starts to fill in a new and emerging picture of biology, the senior author says. That picture may look something like this: RNA hangs out on the cell surface, decorated with sugars. These sugars stick to Siglec proteins that help the immune system distinguish friend from foe.

Scientists have much more to learn before understanding how ­– or if – glycoRNAs are involved in immune signaling, the lead author says.

https://www.hhmi.org/news/some-rna-molecules-have-unexpected-sugar-coating#.YKieVvSNAB0.linkedin

https://www.cell.com/cell/fulltext/S0092-8674(21)00503-1