New study proves they exist

In a groundbreaking study of cell surface biology, Ryan Flynn has uncovered a surprising role for RNA outside the confines of the cell. Flynn’s research, which focuses on cell surface RNA biology, led to the discovery that some RNAs are chemically linked to glycans, complex carbohydrate polymers found on the cell surface.

In 2021, Flynn’s group was the first to report that RNA can be found outside the cell.

“What’s particularly exciting about this discovery is that nucleic acids, such as RNA, have traditionally been thought to be confined within the cell and physically separate from glycobiology,” says Flynn, assistant professor of stem cell and regenerative biology and senior investigator at Boston Children’s Hospital. This discovery challenges the long-held view that nucleic acids are restricted to the intracellular environment, revealing a previously unappreciated layer of complexity in cell surface biology.

In new research published in CellFlynn and his colleagues discovered the mechanism by which RNA is chemically linked to N-glycans. Prior to this research, only proteins and lipids were known to be conjugated to glycans. Flynn’s team has now added RNA to this list, a discovery that has important implications for understanding cell biology.

“Our work proves that there are actually three classes of glycoconjugates: proteins, lipids and RNAs,” he explains. This discovery not only expands the scope of known glycoconjugates, but also opens up new avenues for research into the functions of these glycoRNAs.

The challenge of proving the existence of glycoRNAs

Despite the initial excitement surrounding Flynn’s discovery in 2021, a major challenge remained: proving that these glycoRNAs actually existed as separate molecules. While the team presented data consistent with the existence of glycoRNAs, there was no direct evidence of a chemical link between the RNA and the glycan. This left room for reasonable skepticism within the scientific community, as some wondered whether the results could be attributed to contaminants or other artifacts.

Answering this outstanding question was a top priority; Flynn’s team spent nearly four years working on the problem, developing new techniques to establish a definitive proof.

“The work we’ve done over the last four years in this context has focused on developing two things,” he explains. “On the technical side, we’ve developed a chemical approach to label native glycoRNAs from any RNA source, and then we’ve coupled that with a new style of highly sensitive mass spectrometry that allows for analysis of RNA modifications.”

These advances allowed the team to identify several linkers (direct connections between an RNA base and a sugar), providing the first conclusive evidence for the existence of glycoRNAs, the new report reports. Cell paper.

Implications for cell biology and immunology

The implications of this research go far beyond simply identifying a new molecule. GlycoRNAs, as Flynn’s team discovered, could play a role in immune system interactions.

“In the 2021 paper, we found evidence that glycoRNAs can interact with immune receptors,” he explains. This suggests that glycoRNAs could be a crucial part of how the immune system recognizes and responds to cells, potentially influencing everything from pathogen detection to autoimmune responses.

The presence of glycoRNA on the cell surface could also have broader implications for intercellular communication and signaling. As Flynn explained, “If you’re trying to develop a mechanism to understand why someone has autoimmunity, if you’re not thinking about RNA on the cell surface, you’re going to miss something.”

Flynn’s research revolutionized the field of glycobiology. Before this work, the idea of ​​glycoRNAs was met with skepticism. Today, as Flynn pointed out, the latest edition of the reference book Essentials of Glycobiology refers to glycoRNAs as one of the “big” questions in glycobiology.

This change in focus reflects the growing recognition of glycoRNAs as an important area of ​​study.

“The goal of this study is to generate increased interest in the biology of glycoRNAs and cell surface RNA,” Flynn said. “This study not only expands the understanding of RNA biology, but also opens up new possibilities for research into cell surface interactions and immune system function.”

As the scientific community begins to explore this uncharted territory, the impact of Flynn’s research will likely result in new discoveries and potentially lead to new therapeutic strategies.

Flynn says: “We think this will change the view of the validity of his glycoRNA, because it will be the direct proof that many chemists and glycobiologists have been waiting for.”