SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing

Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2′3′-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity. [Display omitted] •LXR agonists suppress 2′3′-cGAMP-mediated immune response•T0901317 induces the expression of SMPDL3A to restrict cGAMP-STING signaling•SMPDL3A selectively cleaves 2′3′-cGAMP•LXR-mediated SMPDL3A suppresses cGAS-STING signaling in vitro and in vivo The mechanism of how LXR-mediated lipid metabolism is involved in anti-inflammatory effects is unclear. Hou et al. find that LXR agonists induce the expression of SMPDL3A to degrade cGAMP, thereby inhibiting cGAS-STING DNA-sensing pathway.