CM – Some RNA molecules have an unexpected sugar coating


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May 17, 2021

from Howard Hughes Medical Institute

In a surprising find, scientists discovered sugar-coated RNA molecules that adorn the surface of cells.

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These so-called « glycoRNAs » protrude from the outer membrane of mammalian cells and can interact with other molecules there. This discovery, published in the journal Cell on May 17, 2021, improves our current understanding of how the cell deals with RNAs and glycans.

« This was probably the greatest scientific shock of my life, » says the study author Carolyn Bertozzi, a researcher at the Howard Hughes Medical Institute at Stanford University. « Based on the framework by which we understand cell biology, there is no place where glycan sugar and RNA would physically touch. »

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

The Bertozzi team’s first results attracted considerable attention when they posted them on the preprint server in 2019 published. Now the scientists are reporting on a new physical position of the glycoRNAs, which opens up a possible role for the sugar-coated RNAs in immune diseases.

Researchers have been working on « glycobiology » for decades. Among other things, sugars play a key role in cellular communication. Scientists had previously found glycans bound to proteins and fats. Glycomolecules even examine the cell walls of bacteria and fungi and help cells communicate and infect their hosts.

So far, glycobiology and RNA biology have not overlapped. Scientists in both fields use different chemistries and techniques to study their molecules. Study co-author Ryan Flynn, who had spent his school years working on RNA, hadn’t discovered glycobiology until a chance meeting with a student in Bertozzi’s lab. « Glycans are vital in biology and I kind of knew nothing about them, » he says. Flynn was fascinated.

Bertozzi launched Flynn as a postdoc in 2017. The more he learned, the more he wondered if glycans could combine with RNAs. For example, the team knew about a glycan enzyme that could bind RNAs. That made Flynn wonder whether RNA itself could be linked to the sugar. And although most of the glycans are in a cell compartment called the Golgi, some type of glycan mixes in the cytoplasm, where RNA is typically located.

So Flynn went looking for glycoRNAs. He chemically labeled glycans in the cell and then looked for RNAs among the labeled molecules. A hit would mean he found a molecule that contains both RNA and sugar. He conducted experiments for months. In all this time, « I haven’t found anything, » he says. But that wasn’t entirely true.

Flynn had also looked for glycoRNAs in the Golgi. Since RNA was not expected to be present, the test served as a negative control – a way to confirm that his experiment wasn’t detecting RNAs everywhere he looked.

But the negative control kept coming back positive. Somehow, RNAs linked to sugar in the Golgi. The team thought the experiment was contaminated, says Bertozzi. « We have tried to find a million answers to how this sugar is physically associated with RNA. »

Flynn conducted every experiment imaginable to rule out the possibility that the signal came from anything other than RNA. The answer has never changed. He found the glycoRNAs in every cell type that he could grow in the laboratory. He even found them in tissue from mice and more recently discovered glycoRNAs on the cell surface.

« They have used every possible method to confirm the presence of glycan-modified RNA, » says chemical biologist Chuan He, one HHMI researcher at the University of Chicago who was not involved in the new work.

Bertozzi and Flynn attribute the discovery to their unusual overlap of skills. By combining tools and expertise from RNA biology and glycobiology, they were able to discover a phenomenon that was seemingly impossible to miss – if you knew how to look for it.

Meanwhile, researchers in Bertozzi’s lab had a species too Cell surface protein called « Siglecs » was studied. These molecules bind to glycans and play a role in the immune system. Flynn wondered whether Siglecs could also bind to the newly discovered glycoRNAs.

« This was one of those, let’s just try it out, who knows experiments, » says Bertozzi. Flynn tested 12 different Siglec molecules and found that two of them were attached to glycoRNAs.

A literature search revealed that one of the Siglec molecules had previously been linked to the autoimmune disease lupus. Finding connections between these different types of molecules fills a new and emerging picture of biology, says Bertozzi. The picture could look something like this: RNA hangs on the cell surface and is decorated with sugar. These sugars cling to siglec proteins, which help the immune system distinguish friend from foe. Scientists have a lot more to learn before they understand how – or if – glycoRNAs are involved in immune signaling, says Flynn. He currently runs his own laboratory at Boston Children’s Hospital and the Stem Cells and Regenerative Biology Department at Harvard University and plans to investigate these issues.

Bertozzi says the freedom to pursue an unlikely observation has the discovery of the GlycoRNA enables. « HHMI made that available, » she says. « If I were a junior researcher who came across this and was given an NIH scholarship, we’d be laughed out of the student body. »

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