cGAS/
STING signaling plays an essential role in sensing cytosolic
DNA. cGAS activity is regulated by posttranslational modifications and binding partners. cGAS interactome largely includes mammalian or
viral proteins. Whether and how
bacterial proteins bind cGAS to modulate innate immunity remain elusive. Here, we found
streptavidin, a secreted
bacterial protein, selectively bound cGAS to promote
DNA-induced cGAS activation and
interferon-β production. Mechanistically,
streptavidin enhanced
DNA binding and cGAS phase separation, therefore facilitating cGAS activation. Using an HSV-1-infected mouse model, we found
streptavidin nanoparticles facilitated HSV-1 clearance through improving innate immunity. Considering the clinical usage of
streptavidin as an immune stimulant and drug delivery vehicle and its biotechnological usage for
biotin-labeled
protein purification and detection, our studies not only provide an example for a
bacterial protein regulating cGAS activity but also suggest caution needs to be taken when using
streptavidin in various applications given to its ability to induce innate immunity.