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.

脂质代谢与干扰素基因 （STING） DNA 感应通路的环磷酸鸟苷 （GMP）-AMP 合酶 （cGAS） 刺激剂有关，但我们缺乏对这些信号如何整合到内聚免疫代谢程序中的理解。在这里，我们确定了肝脏 X 受体 （LXR） 激动剂是 STING 信号的有效抑制剂。我们表明，LXR 激动剂对脂质代谢的刺激特异性抑制了环状 GMP-AMP （cGAMP）-STING 信号传导。此外，我们开发了环状二核苷酸偶联珠子，用于生化分离宿主效应子以抑制 cGAMP，我们发现 LXR 配体刺激鞘磷脂磷酸二酯酶样 3A （SMPDL3A） 的表达，这是一种 2′3′-cGAMP 降解酶。晶体结构结果表明，cGAMP 类似物诱导 SMPDL3A 的二聚化，而二聚化对 cGAMP 降解至关重要。此外，我们还提供了证据表明 SMPDL3A 切割 cGAMP 以限制细胞培养和小鼠模型中的 STING 信号传导。我们的结果揭示了 SMPDL3A 是一种 cGAMP 特异性核酸酶，并证明了 LXR 相关脂质代谢如何调节 STING 介导的先天免疫的机制。