美国华盛顿大学医学院Daniel B. Stetson团队近期取得重要工作进展，他们研究发现ABCC1转运蛋白能够帮助输出免疫刺激循环二核苷酸cGAMP。这一研究成果2022年9月6日在线发表于《免疫》杂志上。

研究人员鉴定认为ABCC1为小鼠和人类细胞中直接的ATP依赖性cGAMP输出器。他们发现ABCC1过表达增强了cGAMP输出并限制了STING信号，而ABCC1的缺失减少了cGAMP输出并增强了STING信号。ABCC1缺乏加剧了Aicardi-Goutières综合征Trex1^-/-小鼠模型的cGAS依赖性自身免疫。因此，ABCC1介导的cGAMP输出是限制STING的细胞内激活，和改善STING依赖性自身免疫疾病的关键调节机制。

据了解，DNA传感器环GMP-AMP合酶（cGAS）在抗病毒和抗肿瘤免疫中起重要作用。cGAS产生环状GMP-AMP（cGAMP），这是一种可扩散的环二核苷酸，可通过干扰素基因（STING）的衔接蛋白刺激物激活抗病毒反应。cGAMP不能被动地跨细胞膜，但最近的研究表明，细胞外的cGAMP可以作为一种“免疫递质”导入细胞。然而，cGAMP退出细胞的机制仍不清楚。

附：英文原文

Title: ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP

Author: Joanna H. Maltbaek, Stephanie Cambier, Jessica M. Snyder, Daniel B. Stetson

Issue&Volume: 2022-09-06

Abstract: The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumorimmunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotidethat activates the antiviral response through the adaptor protein stimulator of interferongenes (STING). cGAMP cannot passively cross cell membranes, but recent advances haveestablished a role for extracellular cGAMP as an “immunotransmitter” that can be importedinto cells. However, the mechanism by which cGAMP exits cells remains unknown. Here,we identifed ABCC1 as a direct, ATP-dependent cGAMP exporter in mouse and human cells.We show that ABCC1 overexpression enhanced cGAMP export and limited STING signalingand that loss of ABCC1 reduced cGAMP export and potentiated STING signaling. We demonstratethat ABCC1 deficiency exacerbated cGAS-dependent autoimmunity in the Trex1/ mouse model of Aicardi-Goutières syndrome. Thus, ABCC1-mediated cGAMP export is akey regulatory mechanism that limits cell-intrinsic activation of STING and amelioratesSTING-dependent autoimmune disease.

DOI: 10.1016/j.immuni.2022.08.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00399-5