近日，美国德克萨斯大学陈志坚及其研究小组发现PtdIns(3,5)P₂是先天免疫信号中STING的内源性配体。相关论文于2026年2月4日发表于国际顶尖学术期刊《自然》杂志上。

这里课题组发现磷脂酰肌醇3,5-二磷酸(PtdIns(3,5)P₂；也称为PI(3,5)P₂)是STING的内源性配体，与cGAMP一起诱导STING活化。蛋白质组学分析发现STING和PIKFYVE之间存在组成性相互作用，PIKFYVE是一种在哺乳动物细胞中产生PtdIns(3,5)P₂的酶。PIKFYVE的缺失阻断了内质网中STING的转运和TBK1的激活。体外重构揭示了PtdIns(3,5)P₂对cGAMP激活STING的强烈选择性作用。在荧光共振能量转移实验中，PtdIns(3,5)P₂直接与STING结合。与此一致的是，低温电镜显示PtdIns(3,5)P₂促进cGAMP诱导的STING寡聚化，起到分子胶的作用。与PIKFYVE缺失类似，STING中PtdIns(3,5) P₂结合残基的突变在很大程度上阻断了其运输和下游信号传导。这些发现表明PtdIns(3,5)P₂是STING的脂质配体，在先天免疫中起重要作用。

据介绍，暴露于细胞质DNA通过环GMP-AMP（cGAMP）合成酶（cGAS）触发先天免疫反应。在与DNA结合后，cGAS产生cGAMP作为第二信使与干扰素基因刺激因子（STING）结合，STING是一种锚定在内质网（ER）上的信号适配器蛋白。STING随后从内质网通过高尔基体运输到核周囊泡，导致TBK1和IKK激酶激活，随后诱导干扰素和其他细胞因子。

附：英文原文

Title: PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling

Author: Tan, Jay Xiaojun, Lv, Bo, Li, Jie, Li, Tuo, Du, Fenghe, Chen, Xiang, Zhang, Xuewu, Bai, Xiao-chen, Chen, Zhijian J.

Issue&Volume: 2026-02-04

Abstract: Exposure to cytosolic DNA triggers innate immune responses through cyclic GMP–AMP (cGAMP) synthase (cGAS)1,2,3. After binding to DNA, cGAS produces cGAMP as a second messenger that binds to stimulator of interferon genes (STING), a signalling adaptor protein anchored to the endoplasmic reticulum (ER)3,4,5. STING then traffics from the ER through the Golgi to perinuclear vesicle clusters, which leads to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines6,7,8,9. Here we show that phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2; also known as PI(3,5)P2) is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomic analyses identified a constitutive interaction between STING and PIKFYVE, an enzyme that produces PtdIns(3,5)P2 in mammalian cells. Deletion of PIKFYVE blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution uncovered a strong and selective effect of PtdIns(3,5)P2 on STING activation by cGAMP. PtdIns(3,5)P2 bound directly to STING in fluorescence resonance energy transfer assays. Consistently, cryo-electron microscopy revealed that PtdIns(3,5)P2 promotes cGAMP-induced STING oligomerization10, functioning as a molecular glue. Similar to PIKFYVE depletion, mutation of the PtdIns(3,5)P2-binding residues in STING largely blocked its trafficking and downstream signalling. These findings reveal that PtdIns(3,5)P2 is a lipid ligand of STING with essential roles in innate immunity.

DOI: 10.1038/s41586-025-10084-0

Source: https://www.nature.com/articles/s41586-025-10084-0