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

TLDR

The mammalian innate immune system is activated by foreign nucleic acids, and cytoplasmic double‑stranded DNA triggers antiviral responses and macrophage cell death. The authors identified the HIN‑200 protein p202 as a dsDNA‑binding protein that rapidly associates with transfected DNA. Cytoplasmic dsDNA activates caspase 3 and 1, and the study shows that p202 inhibits while AIM2 promotes this activation, indicating that HIN‑200 proteins act as pattern‑recognition receptors for cytoplasmic dsDNA.

Abstract

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.