北京大学蒋争凡研究小组发现，ARMH3介导的PI4KB招募指导抗病毒效应物STING的高尔基体到内体运输和激活。相关论文发表在2023年3月14日出版的《免疫》杂志上。

研究人员报道了STING在高尔基体以外的运输和激活机制。一个全基因组的CRISPR-Cas9筛选确定了犰狳样螺旋结构的蛋白3（ARMH3）对STING的激活至关重要。在环状GMP-AMP（cGAMP）触发的易位后，ARMH3与STING在高尔基体相互作用，并招募磷脂酰肌醇4-激酶β（PI4KB）合成PI4P，后者通过PI4P结合蛋白AP-1和GGA2指导STING高尔基体到内体的运输。通过对其他PI4P结合蛋白的RNAi破坏PI4P依赖的脂质运输，并损害STING的激活。一致的是，紊乱的脂质成分抑制了STING的激活，而异常升高的细胞PI4P导致了不依赖cGAS的STING的激活。Armh3^fl/flLyz^Cre/Cre小鼠在体内易受DNA病毒感染。因此，ARMH3为STING和PIK4B搭桥，产生PI4P用于STING的运输和激活，这种互动在所有真核生物中都是保守的。

据介绍，cGAS-STING途径介导了细胞质DNA触发的先天免疫。STING的激活是由cGAMP诱导的从内质网转运和硫酸化糖胺聚糖诱导的高尔基体聚合启动。

附：英文原文

Title: ARMH3-mediated recruitment of PI4KB directs Golgi-to-endosome trafficking and activation of the antiviral effector STING

Author: Run Fang, Qifei Jiang, Xinying Jia, Zhengfan Jiang

Issue&Volume: 2023/03/14

Abstract: The cGAS-STING pathway mediates cytoplasmic DNA-triggered innate immunity. STING activationis initiated by cyclic-GMP-AMP (cGAMP)-induced translocation from the endoplasmicreticulum and sulfated glycosaminoglycans-induced polymerization at the Golgi. Here,we examine the mechanisms underlying STING transport and activation beyond the Golgi.A genome-wide CRISPR-Cas9 screen identified Armadillo-like helical domain-containingprotein 3 (ARMH3) as critical for STING activation. Upon cGAMP-triggered translocation,ARMH3 interacted with STING at the Golgi and recruited phosphatidylinositol 4-kinasebeta (PI4KB) to synthesize PI4P, which directed STING Golgi-to-endosome traffickingvia PI4P-binding proteins AP-1 and GGA2. Disrupting PI4P-dependent lipid transportthrough RNAi of other PI4P-binding proteins impaired STING activation. Consistently,disturbed lipid composition inhibited STING activation, whereas aberrantly elevatedcellular PI4P led to cGAS-independent STING activation. Armh3fl/fllLyzCre/Cre mice were susceptible to DNA virus challenge in vivo. Thus, ARMH3 bridges STING and PIK4B to generate PI4P for STING transportation andactivation, an interaction conserved in all eukaryotes.

DOI: 10.1016/j.immuni.2023.02.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00078-X