Study shows RNAs act outside cells to guide immune system

Ribonucleic acids (RNA) are the ultimate cellular initiates. They perform several essential tasks, such as transporting genetic instructions from a living organism’s DNA to its protein-producing machinery (a key process in cellular processes) and controlling which genes are activated. All of these processes take place within the safe confines of the cell membrane.

But in recent years, scientists have been surprised to also discover RNA on the surface of cells, well outside their known natural habitat. So what are they doing so far outside of their comfort zone?

One of the key functions of these extracellular RNAs is to guide immune system cells within a type of white blood cell, called neutrophils, to sites of inflammation, according to a new Yale study.

The researchers say they may only be scratching the surface in terms of understanding the previously unexplained roles that RNAs play in living organisms.

Their conclusions are published on January 22 in the journal Cell.

“Neutrophils are the firefighters or first responders to infections or injuries,” said Jun Lu, associate professor of genetics at the Yale School of Medicine (YSM) and co-corresponding author of the new study. “We found that without these RNAs on the cell surface, neutrophils cannot reach their destination.”

It’s also likely that these surface RNAs serve other, still-unclear functions, Lu said, adding, “This is the beginning of a whole new field.”

The Yale research team was also led by Dianqing Wu, the Gladys Phillips Crofoot Professor of Pharmacology at YSM.

RNAs on the surface of cells differ slightly from their cousins ​​found inside cells in that they contain glycans, or sugars, in their structure. In a series of experiments on mice, the Yale team found that when they removed glycoRNAs from the cell surface of neutrophils, the first responders’ cells were no longer able to respond to infections. They also could not migrate out of the bloodstream through the blood vessel walls.

The Yale researchers discovered that glycoRNAs originate from RNAs found inside cells, but the specific process by which they are transported to the cell surface is still being studied. It is possible that regular RNAs inside cells are repurposed for other functions on the cell surface, the researchers say.

Lu explained that more research needs to be done to understand the role of glycoRNAs in the functioning of the human immune system and whether improving this function could help the body fight infections, or alternatively, whether their suppression could help to fight autoimmune diseases.

The paper’s lead authors are postdoctoral associate Ningning Zhang and pharmacology research scientist Wenwen Tang. Zhang, Wu and Lu are all members of the Yale Stem Cell Center.