How a protein cell stops attacking its own DNA

Viruses multiply by injecting their DNA into a host cell. Once inside the intracellular fluid, this foreign material triggers a defense mechanism known as the cGAS-STING pathway. The protein cyclic GMP-AMP Synthase (cGAS), which is also found in the fluid, binds to the invasive DNA to make a new molecule. This, in turn, binds to another protein called Stimulator of Interferon Genes (STING), which induces an inflammatory immune response.

Sometimes the material contained in the liquid – and in contact with the cGAS protein – comes not from a virus, but from the cell itself, for example after the guy has been accidentally called. If this happens, the cGAS-STING path will not be activated. Scientists at EPFL have shown how cells are able to react differently to their own DNA and to genetic material from a pathogen – and to prevent the wrong target. Their discovery, published in a paper in the journal Science, sheds new light on the complex processes at work in the inflammatory response of the body.

The team, led by prof. Andrea Ablasser and worked with colleagues from the laboratories of prof. Beat Fierz and prof. Selman Sakar, discovered new insights into the key role of a small protein known as Barrier-to-Autointegration Factor (BAF). They showed that, by binding to the inoffensive DNA, BAF prevents the cGAS protein from doing the same, thereby stopping the cGAS-STING pathway in its pathways.

BAF strengthens the cell nucleus, connecting the nuclear envelope (as membrane) to the DNA inside. Experiments have shown that when this protein is removed from lab-grown cells, the nucleus breaks down. This invasion releases the genetic material into the intracellular fluid, where it comes into contact with the cGAS protein and triggers the cGAS-STING pathway – just as if it were foreign DNA.

There are several ways to break a core, such as by applying mechanical pressure. But according to Baptiste Guey, one of the paper’s lead authors, only one of these methods – the removal of the BAF protein – induces an immune response. “We can therefore conclude that BAF plays an important role in preventing the cell from attacking its own DNA,” says Guey.

The role of the inhibitor of the protein is very important: Although the cGAS-STING pathway helps the body fight infections, it should also be monitored. “Nuclear breaks sometimes, but cells are able to repair the damage,” says Marilena Wischnewski, another lead author of the paper. “If cGAS bound to the DNA every time that happened, the consequences would be more serious.”

The dangers of an overactive cGAS-STING pathway can be seen in Aicardi-Goutières syndrome: A rare and most fatal genetic disorder that induces an excessive inflammatory response as if the body’s cells were under constant attack from invasive pathogens .

BAF is also believed to play a role in some types of tumor. According to Wischnewski, a high concentration of the protein in cancer cells can be associated with a poorer prognosis. “It may be that BAF makes tumors more resistant,” she explains. “By preventing activation of the cGAS-STING pathway, cancer cells may be able to evade the body’s immune system.”

The protein is found in different amounts in different types of cells. The team plans to delve deeper into these variations as they try to understand how different tissue types respond to infection and inflammation.