HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA

The mammalian innate immune system is activated by foreign nucleic acids. Detection of double- stranded DNA ( dsDNA) in the cytoplasm triggers characteristic antiviral responses and macrophage cell death. Cytoplasmic dsDNA rapidly activated caspase 3 and caspase 1 in bone marrow- derived macrophages. We identified the HIN- 200 family member and candidate lupus susceptibility factor, p202, as a dsDNA binding protein that bound stably and rapidly to transfected DNA. Knockdown studies showed p202 to be an inhibitor of DNA- induced caspase activation. Conversely, the related pyrin domain- containing HIN- 200 factor, AIM2 ( p210), was required for caspase activation by cytoplasmic dsDNA. This work indicates that HIN- 200 proteins can act as pattern recognition receptors mediating responses to cytoplasmic dsDNA.