Our immune system can recognize the difference between our own body chemistry and the chemistry of a pathogenic microorganism. When it’s not working, our bodies can host an intense civil war. Scientists are eager to understand this in more detail, and a newly identified “switch” that disables the foreign DNA sensor could provide important information.

A key part of this discovery, made by a team from the Swiss Federal Institute of Technology in Lausanne, is an enzyme called cyclic GMP-AMP synthase (cGAS). This protein is responsible for identifying invading viruses. It binds to any foreign DNA that becomes dislodged in the cell’s sticky cytoplasm, triggering a response that alerts the body to an invader. We already know that cGAS must be tightly regulated to be kept in check, especially once it enters the cell nucleus. New research identifies a biological switch that marks an enzyme for removal from areas where the immune response is not required.

“Together with previously identified interactions with nucleosomes, our results provide a complete structural model of cGAS nuclear regulation,” the researchers wrote in their published paper.

Scientists found that when cells divide to grow, the nuclear envelope dissolves, allowing easy access to the DNA inside cGAS. Here it binds to DNA packaging units called nucleosomes and coats itself with a protein called BAF, waiting to be needed. In this study, through detailed analysis of laboratory-grown cells, the team identified a protein complex called CRL5-SPSB3 (latest acronym, we promise). A chemical called ubiquitin is added to cGAS to mark it for disposable use.

This is a switch that turns cGAS off when it is not needed, that is, when there is no threat of foreign DNA. Essentially, it stops the enzyme from attacking healthy cells and slowly deactivates it as those cells grow. The part of signaling that controls the immune system’s response is called the interferon or IFN pathway, and the study shows how cGAS and CRL5-SPSB3 are involved in IFN, which is responsible for flipping the switch one way or another.

“These results demonstrate that nuclear levels of cGAS influence cellular IFN tone and reveal a role for CRL5-SPSB3 in cellular innate immunity,” the researchers wrote.

Autoimmune disorders, such as type 1 diabetes and inflammatory bowel disease, occur when the immune system’s controls do not work properly. A new study highlights that one of these controls is worth further study. Now that we know more about how cGAS works, we can develop effective ways to ensure it works properly.

“Our study identifies protein degradation as a determinant of cGAS regulation in the nucleus and provides a structural insight into a cGAS element suitable for therapeutic use,” the researchers wrote.