德克萨斯大学白晓晨小组研究出磷酸肌苷和胆固醇对STING活化的调控。该项研究成果发表在2026年2月4日出版的《自然》上。

在这里，小组证明了cGAMP诱导的STING的高阶寡聚化被磷脂酰肌醇3,5-二磷酸(PtdIns(3,5)P2和PtdIns(4,5)P2强烈增强，而PtdIns4P在较小程度上增强。它们的低温电镜结构显示，PtdInsPs与胆固醇结合在STING二聚体之间的界面上，直接促进了高阶寡聚化。这些结构也解释了STING低聚物对不同PtdInsPs的偏好。突变和生化分析证实了PtdInsPs与胆固醇的结合模式及其在STING激活中的作用。他们的发现揭示了特定脂质介导的STING调节机制，这可能是细胞内运输在决定STING信号传导中的作用的基础。

研究人员表示，干扰素基因刺激因子（STING）是细胞质DNA感知先天免疫途径中必不可少的适配器。STING被DNA传感器cGAMP合成酶（cGAS）产生的环状GMP-AMP （cGAMP）激活。cGAMP诱导的高阶寡聚化和从内质网到高尔基囊泡和后高尔基囊泡的转运对STING激活至关重要。其他研究表明，磷脂酰肌醇磷酸（PtdInsPs）和胆固醇也在STING激活中发挥重要作用，但其潜在机制尚不清楚。

附：英文原文

Title: Regulation of STING activation by phosphoinositide and cholesterol

Author: Li, Jie, Tan, Jay Xiaojun, Chen, Zhijian J., Zhang, Xuewu, Bai, Xiao-chen

Issue&Volume: 2026-02-04

Abstract: Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway1. STING is activated by cyclic GMP–AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS)2,3,4,5. cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation6,7,8,9,10,11. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear12,13,14,15,16,17. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 and PtdIns(4,5)P2, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.

DOI: 10.1038/s41586-025-10076-0

Source: https://www.nature.com/articles/s41586-025-10076-0