The PYRIN domain-only protein POP3 inhibits AIM2-like receptor inflammasomes and regulates responses to DNA virus infections

The innate immune system responds to infections and tissue damage by activating cytosolic sensory complexes called inflammasomes. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the adaptor protein ASC links ALRs to the activation of caspase-1. A controlled immune response is crucial for maintaining homeostasis, but ALR inflammasome regulation is poorly understood. Here, we identified the PYRIN domain (PYD)-only protein 3 (POP3), which competes with ASC for recruitment to ALRs, as an inhibitor of DNA virus-induced ALR inflammasome activation in vivo. Using a mouse model with macrophage-specific POP3 expression, the data emphasizes the importance of ALR inflammasome regulation in the monocytic/macrophage.