数字农科院2.0

ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation

文献类型： 外文期刊

作者： Subhajit Poddar;Samuel D. Chauvin;Christopher H. Archer;Wei Qian;Jean A. Castillo-Badillo;Xin Yin;W. Miguel Disbennett;Cathrine A. Miner;Joe A. Holley;Teresa V. Naismith;W. Alexander Stinson;Xiaochao Wei;Yue Ning;Jiayuan Fu;Trini A. Ochoa;Nehalee Surve;Shivam A. Zaver;Kimberly A. Wodzanowski;Katherine R. Balka;Rajan Venkatraman;Canyu Liu;Kelly Rome;Will Bailis;Yoko Shiba;Sara Cherry;Sunny Shin;Clay F. Semenkovich;Dominic De Nardo;Sunnie Yoh;Elisha D.O. Roberson;Sumit K. Chanda;David J. Kast;Jonathan J. Miner

作者机构：

关键词： antiviral immunity;ArfGAP2;autoinflammation;cGAS;chemokines;cytokines;Golgi trafficking;interferon;SAVI;STING

期刊名称： Cell

ISSN： 0092-8674

年卷期： 2025 年 188 卷 6 期

页码：

收录情况： SCIE（2025版）

摘要： Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.

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