How an innate immune sensor distinguishes friend from foe

How do the molecules involved in activating our immune system discriminate between our DNA and foreign pathogens? Researchers from the Thomä group, in collaboration with EPFL, have deciphered the structural and functional basis of a DNA-sensitive molecule when it comes into contact with the cell’s DNA, providing crucial information on the DNA recognition of self versus non-self. .

The DNA inside our cells is compacted and stored in the nucleus in the form of chromatin (DNA wrapped around histone proteins, forming nucleosomes, the basic unit of chromatin). DNA found outside the nucleus, in the cytoplasm, is an important signal that triggers immune responses that indicate the presence of an intracellular pathogen or a potentially cancerous cell. DNA detection is done by cGAS, an enzyme responsible for recognizing and binding naked DNA. When activated, cGAS synthesizes cyclic GMP-AMP, which in turn initiates the body’s so-called “innate” immune system, the first-line part of our immune system.

Until now, cGAS was thought to function predominantly in the cytoplasm, detecting foreign, non-self, DNA such as viruses. But recent studies have suggested that cGAS is also present within the nucleus. This was disconcerting given the possibility that the enzyme is activated by one’s own DNA triggering an unwanted inflammatory response against one’s own DNA. Intrigued by this observation, researchers from the Thomä group used structural biology as a discovery tool and found that cGAS is present in the nucleus in an inactive state. They collaborated with EPFL’s Ablasser lab to decipher the mechanism of chromatin inactivation of cGAS in cells.

Using the capabilities of the Thomä laboratory in cryo-electron microscopy (cryo-EM), the researchers derived the structure of cGAS bound to a nucleosome. They found that cGAS directly involves the histone proteins of nucleosomes. Once bound to the nucleosome, the cGAS is “trapped” in a state where it is unable to involve or detect naked DNA. So it is not even able to synthesize GMP-AMP and remains inactivated. CGAS, when present in the nucleus of healthy cells, is then inactivated by chromatin and does not participate in innate immune signaling in response to its own DNA.

Ganesh Pathare, postdoc at the Thomä laboratory and one of the first authors of the study, comments: “The structures of the cGAS nucleosomes provide the structural and functional basis for the inhibition of cGAS by chromatin. CGAS is an important protein for the immune response. innate in the cell, necessary for the fight against viruses but also for the detection of transformed or cancerous cells. The activity of cGAS is often misleading even in autoimmune diseases. Our study provides crucial insights into the regulation of cGAS and the mechanism of Self DNA versus non-self DNA recognition. This creates exciting opportunities for future therapeutic interventions in a wide range of diseases. “

This study was published in the November 26, 2020 issue of Nature.