Viruses multiply by injecting their own DNA into a host cell. Once introduced into the intercellular fluid, this foreign material triggers a defense mechanism known as the cGAS-STING pathway. The cyclic protein synthesis GMP-AMP (cGAS), which is also found within the fluid, binds to invading DNA to create a new molecule. This, in turn, binds to another protein called Stimulator of Genes Interferon (STING), which triggers an inflammatory immune response.
Sometimes the material contained inside the fluid ̵1; and in contact with the cGAS protein – does not come from a virus but from the cell itself, for example after the nucleus has accidentally exploded. When this happens, the cGAS-STING path is not activated. Scientists at EPFL have demonstrated how cells are able to react differently to their DNA and to genetic material from a pathogen – and to avoid attacking the wrong target. Their discovery, published in a paper in the magazine science, sheds new light on complex processes at work in the body’s inflammatory response.
The team, led by Prof. Andrea Ablasser and working 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 the Barrier-Autointegration Factor (BAF). They showed that, by binding to non-invasive DNA, BAF prevents the cGAS protein from doing the same, thus stopping the cGAS-STING pathway in its traces.
BAF strengthens the cell nucleus by binding the nuclear envelope (or membrane) to the DNA inside. Experiments have shown that when this protein is removed from cells grown in the laboratory, the nucleus ruptures. This violation releases the genetic material into the intercellular fluid, where it comes in contact with the cGAS protein and causes the cGAS-STING pathway – as if it were foreign DNA.
There are various ways to cause a rupture nucleus, 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 BAF protein – triggers an immune response. “We can therefore conclude that BAF plays a key role in preventing the cell from attacking its own DNA,” says Guey.
The role of the inhibitory protein is quite important: Although the cGAS-STING pathway helps the body fight infections, it must also be kept under control. “The nuclei occasionally rupture, but the cells are able to repair the damage,” says Marilena Wischnewski, another lead author of the paper. “If cGAS binds to DNA every time it 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 usually fatal genetic disease that triggers an exaggerated inflammatory response as if the body cells were under constant attack by invading pathogens.
BAF is also believed to play a role in some types of tumor. According to Wischnewski, a high protein concentration in cancer cells may be associated with a poorer prognosis. “It could be that BAF makes tumors more resistant,” she explains. “By preventing the activation of the cGAS-STING pathway, it can allow cancer cells to bypass the body’s immune system.”
Protein is found in different amounts in different cell types. The team is planning to dig deeper into these variations as they seek to understand how different tissue types respond to infection and inflammation.
Problem innate immunity, cGAS protein and our damaged DNA
“BAF restricts cGAS to nuclear DNA to prevent innate immune activation” science (2020). science.sciencemag.org/cgi/doi… 1126 / science.aaw6421
Provided by the Ecole Polytechnique Federale de Lausanne
citation: How a protein stops cells from attacking their DNA (2020, August 13) Retrieved August 14, 2020 from https://phys.org/news/2020-08-protein-cells-dna.html
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