RNA steps outside the cell to help guide immune responses

RNA is usually portrayed as a molecule that works deep inside the cell, helping to turn genetic information into proteins. But new research led by Utrecht University scientist Jack Li shows that RNA also plays an active role on the outside of cells. There, it appears to help immune cells recognize their targets. These results may open new perspectives for understanding, and eventually steering immune responses in diseases such as cancer.

For decades, biology textbooks have taught that RNA works inside the cell. Here they translate genetic information into proteins or regulate processes deep within the cell’s interior. But new research led by chemical biologist Jack Li shows that RNA also plays an unexpected role on the outside of cells, where it can influence how immune cells recognize their targets.

The discovery was the result of a close collaboration between researchers from Utrecht University, Delft University of Technology, Leiden University Medical Center.
 

RNA steps outside the cell

The study, published in the journal Molecular Cell, uncovers how RNA molecules can survive on the cell surface and what they are doing there. “Conventionally biologist think RNA must be within the cells,” Li says. “But recently there are views showing these molecules can also make their way to the surface and perhaps do some regulation outside of the cell.”

Fundamental questions

That simple observation raised a series of fundamental questions. How does RNA remain attached to the outside of a living cell, where enzymes that destroy RNA are abundant? And if it is there, is it just debris from deceased cells, or does it actually do something meaningful?

How does fragile RNA survive on the cell surface, and what does it do there?

Li and his collaborators set out to answer those questions by developing a new molecular tool. This tool can detect RNA on the surface of living cells without damaging them. Using this tool together with large-scale genetic screening and advanced protein analysis, the team pieced together a detailed molecular picture.

How RNA stays attached to the cell surface

They found that cell-surface RNA is anchored by long sugar molecules called heparan sulfate. These are common components of the cell membrane and help organize molecules at the cell’s outer surface. RNA-binding proteins then connect the RNA to these sugar chains, forming a stable molecular assembly. “The sugar provides the support, and the proteins act as a bridge to fix the RNA onto the cell surface,” says Li.

Surface-bound RNA as a matchmaker

The researchers then asked why this surface-bound RNA is actually there and if it has any specific tasks. One assumption was that the RNA affects how cells interact with other molecules. Immune cells constantly scan the body for infected or cancerous cells, and small changes in how receptors bind can determine whether a cell is attacked or ignored.

RNA helps immune cells decide whether to attack or stand down

Li’s team showed that cell-surface RNA can help bring together an immune receptor on natural killer cells with its partner on a target cell. When the RNA was removed, this binding can become much less efficient.

In other words, RNA can act as a kind of molecular matchmaker at the cell surface, subtly tuning how immune cells recognize other cells. Until now, scientists thought this kind of communication was handled mainly by proteins and sugars. RNA simply wasn’t part of the picture.

Far-reaching implications for therapies

In the long run, implications could be far-reaching, especially in cancer and immunology. Many cancer cells express immune checkpoint molecules that tell immune cells to stand down. If cell-surface RNA helps regulate these interactions, it could one day become a new target for therapies. “We’re adding a whole new layer to this crosstalk between cancer cells and immune cells,” Li says. “RNA may be playing a role here that we didn’t notice before.”

We’re adding a whole new layer to this crosstalk between cancer cells and immune cells

Li is careful not to overstate the medial implications of this work. The study primarily focuses on fundamental mechanisms, not immediate medical applications.

How does RNA get there?

One of the biggest open questions remains how RNA gets to the cell surface in the first place. “It is still unknown whether the RNA comes from inside the cell or whether it is captured from the outside, for example from surrounding cell debris,” says Li. 

Understanding this step will be crucial for determining when and where cell-surface RNA plays a role in the body and how it might be manipulated in the future.

Many more roles for RNA

That mystery is now one of the main directions for Li’s future research, alongside exploring how widespread and important cell-surface RNA regulation might be. “This must be a tip of the iceberg,” Li says. “We currently don’t know how many cell-surface proteins are regulated by RNA and how many are not.”