BAF restricts cGAS on nuclear DNA to prevent innate immune activation

A loose BAF puts its foot on the cGAS A signaling pathway in vertebrates called cGAS-STING detects the presence of intracellular DNA as a surrogate for both cellular damage and viral infection. At the same time, sensing of self-DNA must be suppressed to prevent the development of autoimmune responses. Guey et al. identify barrier-to-autointegration factor 1 (BAF) as a protein that intrinsically competes with the cGAS component of this pathway for binding to genomic self-DNA. When there is a breakdown in nuclear compartmentalization, cytosolic cGAS enzymatic activity is prevented because of BAF. This work suggests that the regulation of DNA detection by the innate immune system relies on more complex mechanisms than simple physical separation alone. Science, this issue p. 823 A safeguard mechanism protects cells against aberrant immune responses toward their own genomic DNA. The appearance of DNA in the cytosol is perceived as a danger signal that stimulates potent immune responses through cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). How cells regulate the activity of cGAS toward self-DNA and guard against potentially damaging autoinflammatory responses is a fundamental biological question. Here, we identify barrier-to-autointegration factor 1 (BAF) as a natural opponent of cGAS activity on genomic self-DNA. We show that BAF dynamically outcompetes cGAS for DNA binding, hence prohibiting the formation of DNA-cGAS complexes that are essential for enzymatic activity. Upon acute loss of nuclear membrane integrity, BAF is necessary to restrict cGAS activity on exposed DNA. Our observations reveal a safeguard mechanism, distinct from physical separation, by which cells protect themselves against aberrant immune responses toward genomic DNA.