POP3 is a novel inhibitor of ALR inflammasomes and controls host defense to DNA virus infections (INM6P.411)

Abstract

Abstract 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 through PYRIN domain (PYD)-PYD interaction, links ALRs to the activation of caspase-1 and subsequent maturation of the proinflammatory cytokines IL-1β IL-18 and induction of pyroptotic cell death. A controlled inflammasome response is crucial for maintaining homeostasis, whereas excessive and uncontrolled cytokine production contributes to autoinflammatory diseases. However, ALR inflammasome regulation is poorly understood. Here, we identified the type I interferon (IFN)-inducible PYD-only protein 3 (POP3) as a binding partner of ALRs. POP3 competes with ASC for recruitment to ALRs and thereby inhibits DNA virus-induced ALR inflammasome activation and IL-18 and IFN-γ-dependent host defense in vivo. A mouse model with macrophage-specific POP3 expression recapitulates global AIM2 deficiency and thus, emphasizes the importance of ALR inflammasome regulation in the monocytic/macrophage lineage. Collectively, we show that POP3 represents one of the type I IFN response factors that regulate human and mouse ALR inflammasomes in macrophages within a type I IFN-regulatory loop.