An unexpected discovery of glycoRNAs on the cell surface

Credit: Emily M. Eng/R. Flynn et al./Cell 2021

Recently scientists have found sugar-coated RNA molecules, called glycoRNAs. This discovery is reported in the journal Cell.

“This was probably the biggest scientific shock of my life,” says study author Carolyn Bertozzi, a Howard Hughes Medical Institute Investigator at Stanford University. “Based on the framework by which we understand cell biology, there’s no place where glycan sugars and RNA would physically touch each other"

RNA is made in the nucleus and transported to the cytoplasm where it is used as a template for proteins. Until now, scientists thought glycans were kept separate, but this new study suggests that they meet up and go to the outer membrane where they interact with other molecules. 

Sugars serve a key role in cellular communications, and glycans have been found attached to proteins and fats. Until now, glycobiology and RNA biology did not overlap. And nobody was expecting to find glycoRNAs/ in 2017, Bertozzi brought in Flynn as a postdoc, and he wondered if RNA itself could bind with sugar, so in order to fin glycoRNAs, he chemically tagged glycans within the cell and then looked for RNAs among the tagged molecules. After running experiments for months, after all the time, he didn't found anything, at least that was what he thought, he was looking for glycoRNAs in the cytoplasm, although glycans reside in Golgi, RNA doesn't dwell there. So to have a negative control, he ran tests in Golgi, and the negative control kept coming back positive, somehow RNAs were bonding with sugars in the Golgi. 

The team thought that the experiment must have been contaminated, and they conducted several tests to rule out the possibility that the signal was coming from something else besides RNA, but he found glycoRNAs in every cell he could grow in the lab, even in tissues from Mice, and recently on the cell surface. 

Credit: R. Flynn et al./Cell 2021

Meanwhile, researchers in Bertozzi’s 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. Flynn wondered if Siglecs could also bind with glycoRNAs. A search revealed that one of the Siglec molecules had been previously linked to autoimmune disease lupus. These new discoveries started to form an entirely new view, glycoRNAs emerge on the cell surface, and the sugars on the RNA stick to Siglec protein that can help the immune system distinguish friend from foe. 

They still have to learn more that if glycoRNAs are involved in immune signaling or not. And currently, Flynn is running his own lab at Boston Children' hospital and Harvard University's stem cell and regenerative biology departments in order to look more into this.

Reference: DOI:10.1016/j.cell.2021.04.023

Source: Howard Hughes Medical Institute