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How a protein prevents cells from attacking their own DNA


A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color coded in pink, orange, purple and yellow. Credit: NHGRI

Viruses multiply by injecting their DNA into a host cell. When it enters 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 inside the fluid, binds to the invading DNA to create 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 inside 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 has accidentally ruptured. When this happens, the cGAS-STING path is not activated. Researchers at the EPFL have demonstrated how cells are able to respond differently to their own DNA and to genetic material from a pathogen – and to avoid attacking the wrong target. Their discovery, which was published in a paper in the journal Science, sheds new light on the 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, revealed new insights into the key role of a small protein known as the Barrier-to-Autointegration Factor (BAF). They showed that BAF by binding to the inoffensive DNA prevents the cGAS protein from doing the same, thus stopping the cGAS-STING pathway in its traces.

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

There are different ways to make a core explode, e.g. 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 a key role in preventing the cell from attacking its own DNA,” Guey says.

The inhibitor role of the protein is very important: Although the cGAS-STING pathway helps the body fight infections, it must also be kept under control. “Kernels break down occasionally, 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 it happened, the consequences would be more severe.”

The dangers of an overactive cGAS-STING pathway can be seen in Aicardi-Gouti√®res syndrome: a rare and usually fatal genetic disorder that induces an excessive inflammatory response, as if the body’s cells were under constant attack from invading pathogens.

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

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

Study innate immunity, cGAS protein and our own damaged DNA

More information:
“BAF restricts cGAS on nuclear DNA to prevent congenital immune activation” Science (2020). science.sciencemag.org/cgi/doi … 1126 / science.aaw6421

Provided by the Ecole Polytechnique Federale de Lausanne

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

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