Intracellular recognition of lipopolysaccharide (LPS) by mouse caspase-11 or human caspase-4 is a vital event for the activation of the noncanonical inflammasome. Whether negative regulators are involved in intracellular LPS sensing is still elusive. Here we show that adipose triglyceride lipase (ATGL) is a negative regulator of the noncanonical inflammasome. Through screening for genes participating in the noncanonical inflammasome, ATGL is identified as a negative player for intracellular LPS signaling. ATGL binds LPS and catalyzes the removal of the acylated side chains that contain ester bonds. LPS with under-acylated side chains no longer activates the inflammatory caspases. Cells with ATGL deficiency exhibit enhanced immune responses when encountering intracellular LPS, including an elevated secretion of interleukin-1β, decreased cell viability and increased cell cytotoxicity. Moreover, ATGL-deficient mice show exacerbated responses to endotoxin challenges. Our results uncover that ATGL degrades cytosolic LPS to suppress noncanonical inflammasome activation.

小鼠 caspase-11 或人 caspase-4 对脂多糖 (LPS) 的细胞内识别是非经典炎症小体激活的重要事件。负调节因子是否参与细胞内 LPS 传感仍不清楚。在这里，我们证明脂肪甘油三酯脂肪酶（ATGL）是非典型炎症小体的负调节因子。通过筛选参与非典型炎症小体的基因，ATGL 被确定为细胞内 LPS 信号传导的负面参与者。ATGL 结合 LPS 并催化去除含有酯键的酰化侧链。侧链未充分酰化的 LPS 不再激活炎症性半胱天冬酶。ATGL 缺陷的细胞在遇到细胞内 LPS 时表现出增强的免疫反应，包括白细胞介素 1β 分泌增加、细胞活力降低和细胞毒性增加。此外，ATGL 缺陷小鼠对内毒素的挑战表现出加剧的反应。我们的结果表明 ATGL 降解胞质 LPS 以抑制非典型炎症小体激活。