Study unveils how our cells outsmart invaders without turning against us

The human immune system is a sophisticated network of cells and proteins created to defend against dangerous infections, and cells continuously repel invaders in a microscopic war raging inside human bodies. Cyclic GMP-AMP Synthase (cGAS), an enzyme that functions as a sentinel by identifying foreign DNA and triggering an immune response, is one of its essential parts.

The immune system necessitates meticulous regulation to avert cGAS from erroneously targeting the body's own tissues, thereby precipitating autoimmune disorders, which currently afflict approximately 10% of the global population.

Parts of this process have been partially explained by earlier research. The nuclear envelope, which surrounds the cell's nucleus, ruptures during mitosis, the process of cell division, and cGAS swiftly moves into the nucleus. There, it binds to nucleosomes, the fundamental structural component of the cell's DNA packaging, and is then covered by the BAF protein.

All of this ensures that cGAS remains stationary and inactive and does not unintentionally interact with the cell's DNA. It stands for a deft balancing act between immune preparedness and preserving the genetic integrity of the cell. The question is how the cell juggles this with its other regular tasks.

Andrea Ablasser's group at EPFL has published a new study in the journal Nature that clarifies the regulation of cGAS, particularly during mitosis, a crucial stage of cell division.

The researchers observed how cGAS is specifically broken down in the nucleus to stop it from mistakenly reacting to the cell's DNA using cutting-edge imaging and molecular techniques. They discovered that the CRL5–SPSB3 protein complex, which identifies a particular motif in cGAS and tags it in the nucleus for destruction, mediates the process.

The researchers visualized the atomic-level interactions between cGAS and the protein complex by applying structural biology, biochemistry, and cell biology techniques.

More specifically, ubiquitin is added to cGAS by CRL5–SPSB3. As its name implies, ubiquitin is present in all eukaryotic cells and can mark other proteins for death. Once the threat of an invasion has been eliminated, the ubiquitination of cGAS also designates it for destruction, thereby deactivating the sentinel.

This work highlights the complexity of the immune system's regulatory networks by mapping out the regulation of cGAS within cell nuclei by elucidating the structure of the cGAS-SPSB3 complex.

Beyond fundamental research, the implications enable researchers to investigate novel approaches to treating conditions in which the immune system is either hyperactive, as in autoimmune diseases, or underactive, as in cancer or chronic infections. Modulating cGAS activity, for instance, may improve the efficacy of immunotherapies for cancer or offer fresh strategies for averting autoimmune diseases.