Barrier-to-autointegration factor protects against the cGAS-STING response to chromatin bridges.

Cellular damage or stress can lead to disorganization, mislocalization or damage to self-DNA that can activate intracellular innate immune response mechanisms. Micronuclei, such as can occur following mitotic defects, have been proposed as a source of DNA capable of activating the cGAS-STING pathway, resulting in IRF3-dependent proinflammatory transcription. However, to what extent micronuclei per se or other concurrent defects contribute to the cGAS-STING response remains unclear. To better understand the ability of post-mitotic defects to induce this response, we compared the effects resulting from inhibition of the Spindle-Assembly Checkpoint (through MPS1 inhibition) or interference with nuclear reassembly (through inactivation of BAF). We found that combining both perturbations synergistically enhances the cGAS-STING response. This effect is not due to an increase in post-mitotic nuclear deformations including micronucleation and lobulation but instead correlates with an increase in destabilized chromatin bridges resulting in structures that potently recruit cGAS. Our results suggest that by stabilizing chromatin bridges, BAF contributes to preventing their degeneration into cGAS-activating chromatin structures. This work helps better understand how the innate immune system detects mitotic defects.