A loose BAF places the foot on the cGAS
A signaling pathway in vertebrates called cGAS-STING detects the presence of intercellular DNA as a substitute for both cell damage and viral infection. At the same time, the sense of self-DNA must be suppressed to prevent the development of autoimmune responses. Gueye et al. identify barrier factor against autointegration factor (BAF) as a protein that essentially competes with the cGAS component of this pathway to bind to genomic self-DNA. When there is a cleavage in the nuclear cleavage, cytosolic cGAS enzymatic activity is prevented due to 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
The appearance of DNA in the cytosol is perceived as a danger signal that stimulates potent immune responses through cyclic monophosphate-guanosine monophosphate-adenosine monophosphate (cGAS) synthesis. How cells regulate cGAS activity against self-DNA and guard against potentially impaired autoimmune responses is a fundamental biological question. Here, we identify factor 1barrier to autointegration (BAF) as a natural antagonist of cGAS activity in genomic self-DNA. We show that BAF dynamically terminates cGAS for DNA binding, thus stopping the formation of DNA-cGAS complexes that are essential for enzymatic activity. Following acute loss of nuclear membrane integrity, BAF is required to limit cGAS activity in exposed DNA. Our observations reveal a defense mechanism, distinct from physical division, by which cells defend themselves against the immune response to genomic DNA.