The role of RNAs keeps growing and growing. New research shows that cell surface RNAs are critical in neutrophil recruitment to inflammatory sites. These “glycoRNAs” on the cell surface of neutrophils facilitate binding to endothelial cells and transendothelial migration. Together with previous research demonstrating that glycoRNAs can be found in many cell types, it’s possible that glycoRNAs could play important functions across multiple cell types and in multiple biological settings.

The research article “Cell surface RNAs control neutrophil recruitment” was published in Cell.

A short history of glycoRNAs

Two recent studies detected the presence of RNAs on the outer cell surface of mammalian cells. The cell surface represents a topologically different space from the nucleus and cytoplasm, where most cellular RNAs are located, thus raising important questions on cell surface RNAs’ functions and how they are produced and transported.

A 2020 Genome Biology article described a group of membrane-associated extracellular RNAs (maxRNAs) found in human circulating blood cells, mostly monocytes. The authors suggested that these RNA species might be captured from RNAs released by dying cells. The in vivo function of maxRNAs, their production, and their recognition mechanisms have not been identified.

A 2021 Cell article discovered that some small RNAs in cancer cell lines and embryonic stem cells have N-glycosylation. Many N-glycosylated small RNAs, termed glycoRNAs, are found on cell membranes. GlycoRNA production depends on several enzymes that also help with protein glycosylation. However, the glycoRNA function and production study is nascent and remains unclear.

Neutrophil glycoRNAs confer lectin protein specificity

Co-lead authors Ningning Zhang and Wenwen Tang used neutrophils to study the function of cell surface RNAs because these innate immune cells move quickly from the bloodstream to inflammatory sites in response to tissue damage, a process that involves lots of interactions between cells. They focused on neutrophils to study cell surface RNAs’ expression, function, and regulatory mechanisms.

The Yale research team demonstrated that the lectin P-selectin (Selp), but not Sele, can recognize at least a subset of neutrophil glycoRNAs. P-selectin recognizes ligands with sialic acid moieties and can strongly bind only sialic acid-containing glycoproteins.

Only a few glycoproteins or glycolipids have been suggested as possible P-selectin ligands. P-selectin glycoprotein ligand-1 (PSGL-1) is the one that has been studied the most and shown to work as a P-selectin ligand in living cells. However, Sele is also capable of recognizing PSGL-1. These results show that P-selectin can bind to RNA and raise the idea that glycoRNAs might make ligand specificity possible for lectin proteins that are very similar.

GlycoRNAs were found to be surprisingly stable despite being primarily on the outer cell surface of neutrophils, as evidenced by their low turnover rates. The researchers estimated from experiments that the average half-life of neutrophil glycoRNAs is 24 hours or more.

These findings also suggest that the RNA part of cell surface glycoRNAs is strongly blocked from RNase access, most likely by proteins on the cell surface that have not been found yet. On the other hand, P-selectin can bind to the glycan component.

This protection model fits their observation that the glycan fraction, not the RNA fraction, controls how neutrophils stick to and move through an endothelial layer. This model could also explain why RNAs can be located on the outer cell membrane without being easily degraded.

While glycoRNA production requires many glycosylation enzymes that are important for the N-glycosylation of proteins, the discovery of the role of Sidt RNA transporters—which can be present on the membranes of intracellular organelles to facilitate RNA entry into such organelles to be glycosylated—in controlling glycoRNA levels makes a link that is unique to RNA.

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