美国宾夕法尼亚大学的Jonathan J. Miner课题组取得一项新突破。他们的最新研究提出了ArfGAP2促进STING质子通道活性、细胞因子转运和自身炎症。相关论文于2025年2月12日发表于国际顶尖学术期刊《细胞》杂志上。
由于主题pH影响高尔基酶活性、蛋白质成熟和运输，小组假设STING质子通道活性影响多种高尔基功能。课题组人员发现STING介导的质子外排非转录调节高尔基体转运蛋白质货物。这一过程需要高尔基蛋白相关蛋白ArfGAP2，这是一种细胞类型特异性的STING介导的质子外排和信号传导的双重调节剂。在SAVI小鼠中，造血细胞和内皮细胞中ArfGAP2的缺失，可显著降低STING介导的细胞因子和趋化因子分泌、免疫细胞激活和自身炎症病理。其中，ArfGAP2促进STING介导的造血细胞信号和细胞因子释放，在自身炎症性疾病的发病机制中发挥重要作用。
研究人员表示，干扰素基因刺激因子（STING）向胞质DNA传感器环鸟苷单磷酸腺苷合成酶（cGAS）下游传递信号，导致细胞因子的转录上调。然而，STING信号通路的组成部分，如IRF3和IFNAR1，对于STING功能获得（婴儿期发作的STING相关血管病变[SAVI]）小鼠的自身炎症性疾病并不是必需的。最近的发现表明，STING还可以作为质子通道，使高尔基体脱酸。
附：英文原文
Title: ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation
Author: 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
Issue&Volume: 2025-02-12
Abstract: 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.
DOI: 10.1016/j.cell.2025.01.027
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00096-0