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How a protein prevents cells from attacking their own DNA


A representation of the double helix structure of DNA. The four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Image credit: NHGRI

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

Sometimes the material contained in the liquid ̵

1; and in contact with the cGAS protein – does not come from a virus but from the cell itself, for example after the nucleus is accidentally torn. In this case the cGAS-STING path is not activated. EPFL scientists have shown how cells can react differently to their own DNA and to genetic material from a pathogen – and avoid attacking the wrong target. Your discovery, published in an article in the magazine sciencesheds new light on the complex processes involved in the body’s inflammatory response.

The team, led by Prof. Andrea Ablasser and in collaboration 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-to-Autointegration Factor (BAF) is. They showed that by binding to the harmless DNA, BAF prevents the cGAS protein from doing the same, thereby stopping the cGAS-STING pathway in its tracks.

BAF strengthens the cell nucleus and connects the nuclear envelope (or membrane) with the DNA inside. Experiments have shown that when this protein is removed from cells grown in the laboratory, the core ruptures. This injury releases the genetic material into the intracellular fluid, where it comes in contact with the cGAS protein and triggers the cGAS-STING pathway – as if it were foreign DNA.

There are several ways of causing a core to burst, for example by applying mechanical pressure. However, according to Baptiste Guey, one of the lead authors of the paper, only one of these methods – removing the BAF protein – induces 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 protein’s inhibitory role is vital: while the cGAS-STING pathway helps the body fight off infection, it also needs to be kept in check. “Nuclei occasionally burst, but cells can repair the damage,” says Marilena Wischnewski, another lead author of the paper. “If cGAS were bound to DNA every time, the consequences would be more severe.”

The dangers of an overactive cGAS-STING signaling pathway can be observed in Aicardi-Goutières syndrome: a rare and usually fatal genetic disorder that causes an excessive inflammatory response, as if the body’s cells were constantly being attacked by invading pathogens.

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

The protein is found in different amounts in different cell types. The team plans to dig deeper into these variations to understand how different tissue types respond to infection and inflammation.

Examination of innate immunity, cGAS protein and our own damaged DNA

More information:
“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

Quote: How a protein prevents cells from attacking their own DNA (2020, August 13), accessed on August 14, 2020 from https://phys.org/news/2020-08-protein-cells-dna.html

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