One of the central components of the immune system is the enzyme cyclic GMP-AMP synthase (cGAS), which acts as a guard, detecting foreign DNA and initiating an immune response. If cGAS is not properly regulated, it will mistakenly attack the body’s own tissues, leading to autoimmune disorders. Previous studies have not been fully able to reveal how cGAS does not mistakenly interact with the cell’s own DNA. Now, a study in mice by the École Polytechnique Fédérale de Lausanne (EPFL) sheds light on how cGAS is regulated, especially during the critical phase of cell division known as mitosis.

Previous studies have revealed little about how this happens. During cell division—mitosis— the membrane that protects the cell’s nucleus, the nuclear envelope, breaks down and cGAS quickly relocates into the nucleus. There, it attaches itself to nucleosomes and becomes covered by another protein called BAF. All this ensures that cGAS stays inactive and fixed in place, and does not mistakenly interact with the cell’s own DNA.

The new study, “The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation,” published in Nature, demonstrates how cGAS is selectively broken down in the nucleus, preventing it from mistakenly responding to the cell’s own DNA.

“Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA,” the researchers wrote. “However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells.”

Using advanced imaging and molecular techniques, the researchers discovered that the process is mediated by a protein complex known as CRL5–SPSB3, which recognizes a specific motif in cGAS and tags it in the nucleus for destruction. Using structural biology, biochemistry, and cell biology, the researchers then visualized the interactions between cGAS and the protein complex at the atomic level.

CRL5–SPSB3 adds a protein called ubiquitin to cGAS. The ubiquitination of cGAS also marks it for destruction, effectively inactivating the sentinel once the threat of an invader has been neutralized. By elucidating the structure of the cGAS-SPSB3 complex, the study maps out how cGAS is regulated within the nucleus of cells.

The new findings will help scientists explore new strategies for treating diseases where the immune system is either overactive, such as in autoimmune diseases, or underactive, as in cases of chronic infections or cancer.

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