清华大学张从刚研究组揭示了SMPDL3A是一种由肝脏X受体(LXR)介导的脂质代谢诱导的环GMP-AMP (cGAMP)降解酶，用于限制环鸟苷单磷酸(GMP)-AMP合成酶(cGAS)- 干扰素基因刺激因子(STING)  DNA传感。这一研究成果发表在2023年10月26日出版的国际学术期刊《免疫》上。

他们已经确定LXR激动剂作为STING信号的有效抑制剂。他们发现LXR激动剂刺激脂质代谢特异性抑制cGAMP-STING信号。此外，他们开发了环二核苷酸偶联小珠来生物化学分离抑制cGAMP的宿主效应物，他们发现LXR配体刺激鞘磷脂磷酸二酯酶样3A (SMPDL3A)的表达，SMPDL3A是一种2 ' 3 ' -cGAMP降解酶。

晶体结构表明，cGAMP类似物诱导SMPDL3A的二聚化，而二聚化对cGAMP的降解至关重要。此外，他们已经在细胞培养和小鼠模型中提供了SMPDL3A切割cGAMP以限制STING信号传导的证据。他们的研究结果揭示了SMPDL3A是cgamp特异性核酸酶，并证明了LXR相关的脂质代谢如何调节sting介导的先天免疫的机制。

研究人员表示，脂质代谢与cGAS-STING DNA传感途径有关，但我们对这些信号如何整合到一个有凝聚力的免疫代谢程序缺乏了解。

附：英文原文

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

Author: Yanfei Hou, Zhimeng Wang, Peiyuan Liu, Xubiao Wei, Zhengyin Zhang, Shilong Fan, Lulu Zhang, Fangping Han, Yikang Song, Ling Chu, Conggang Zhang

Issue&Volume: 2023-10-26

Abstract: Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMPsynthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but ourunderstanding of how these signals are integrated into a cohesive immunometabolicprogram is lacking. Here, we have identified liver X receptor (LXR) agonists as potentinhibitors of STING signaling. We show that stimulation of lipid metabolism by LXRagonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover,we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectorsfor cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelinphosphodiesterase 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 providedevidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture andmouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstratea mechanism for how LXR-associated lipid metabolism modulates STING-mediated innateimmunity.

DOI: 10.1016/j.immuni.2023.10.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00441-7