Science

Cell Surface RNA Helps Neutrophils Get Around



RNA is considered a stay-at-home type of molecule, typically comfortably confined inside the cell’s inside. So, when RNA molecules had been detected on the floor of a number of cell sorts, researchers questioned what objective they may serve. A latest research has revealed one among their features: mobilizing immune cells to inflamed tissue. 1

Printed final month in Cell, a Yale College group led by geneticist Jun Lu  and pharmacologist Dianqing Wu described how cell floor RNA helps neutrophils latch onto endothelial cells and infiltrate tissue. Eradicating the molecules prevents the immune cells from reaching inflammatory websites in mice, highlighting their function within the immune system’s response to potential threats.

After remaining a thriller for thus lengthy, it’s encouraging that researchers are listening to the features of cell-surface RNAs, acknowledged Carolyn Bertozzi, a biochemist at Stanford College, who was not concerned within the new research. “I’m actually excited that this group began pondering of [them] as a possible mediator of neutrophils.”

Proof of cell-surface RNAs first came to light in 2020, once they had been detected on immune cells in human blood.2 The next 12 months, Bertozzi’s group discovered the molecules littering the floor of most cancers cells and stem cells, the place they’re welded to a sugar chain.3 Like glycoproteins and glycolipids, this new class of molecule, christened glycoRNAs, appeared to bind to immune receptors, pointing to potential immunoregulatory features.

When Lu got here throughout these papers, he responded with a wholesome dose of skepticism. In any case, he reasoned that any uncovered RNA ought to be torn aside by RNases, RNA-degrading enzymes that roam the blood plasma.

“I questioned the way it was even potential. On the time we had a postdoc becoming a member of the lab and we mentioned perhaps you need to spend two months proving them unsuitable, then transfer onto one thing else,” mentioned Lu with a smile.

His group started by utilizing a chemical marker known as biotin to label any sugar chains current on the neutrophil floor, tagging glycoproteins, glycolipids, and—doubtlessly—glycoRNAs. With out rupturing the cell membrane, they purified RNA from labeled cells after which utilized RNase at concentrations far larger than sometimes discovered within the human physique. If the enzyme diminished the biotin sign, some sugars on the cells have to be sure to extracellular RNA. To Lu’s shock, the sign vanished, confirming the presence of glycoRNAs on the cell floor. 

If glycoRNAs share comparable features to glycoproteins and glycolipids, they could assist immune cells attain inflammatory websites. To check this, the researchers dyed some neutrophils pink and degraded their extracellular glycoRNAs utilizing RNase. They labeled different neutrophils inexperienced however left their floor RNAs intact. After injecting the dyed cells right into a mouse that had stomach irritation, Lu’s group discovered that the cells missing glycoRNAs had been much less prone to attain the abdomen.

To infiltrate tissue, neutrophils should first latch onto exterior cells after which traverse via a number of cell layers. Lu questioned whether or not glycoRNAs contributed to each phases of this course of, so his group positioned neutrophils on one facet of a cultured endothelial layer and a chemoattractant on the opposite. Immune cells missing glycoRNAs confirmed much less adhesion and diminished migration via the cell layer in vitro. With out the endothelial barrier, the cells migrated usually, suggesting that glycoRNAs don’t have an effect on cell mobility. 

To uncover how neutrophil glycoRNAs mediate attachment to endothelial cells, the researchers break up the molecule into its sugar and RNA elements. Saturating the identical cell tradition system with glycans blocked the immune cells from migrating via the endothelial layer, whereas RNA saturation had no impact. The findings prompt that—in an identical method to different glycoconjugates—the glycan portion latches onto endothelial cells, whereas the RNA tethers the sugar to the membrane.

Serving as a scaffold, the precise RNA sequence—no less than on this context—seems much less vital, the researchers defined. “There could also be a hidden life for a sequence-based operate too,” Lu mentioned. “That is simply the tip of the iceberg.” 

The researchers questioned whether or not glycoRNAs originate intracellularly or from captured fragments launched extracellularly by dying cells. To discover this, they once more labeled teams of neutrophils pink or inexperienced. They chemically labeled the glycoRNAs on solely the inexperienced cells. After culturing the cells collectively for 3 days, the group detected the chemical tags on solely inexperienced cells, suggesting that the RNA is produced in-house reasonably than transferred from the exterior setting.

Sequencing the glycoRNA molecules turned up hits for ribosomal RNA, switch RNA, and small nucleolar RNAs, suggesting that they could be repurposed fragments of noncoding nucleic acids. But the foundations that decide which bits of RNA find yourself on the membrane, and the way they’re shielded from degradation, are unclear. 

These are questions that the Yale group hopes to deal with in future work. The researchers additionally plan to research whether or not glycoRNA expression is altered in varied illness states. However owing to a scarcity of real-time detection strategies, this shall be experimentally difficult. “Methodologies have to be improved earlier than we are able to deal with a lot of these questions,” Wu mentioned.

References

  1. Zhang N, et al. Cell surface RNAs control neutrophil recruitment. Cell. 2024;187:846-860.
  2. Huang N, et al. Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interactions.Genome Biol. 2020;21,225.
  3. Flynn RA, et al. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell. 2021;184, 3109-3123.e22.



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