Departments of Immunology and Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Immunity. 2022 Oct 11;55(10):1799-1812.e4. doi: 10.1016/j.immuni.2022.08.006. Epub 2022 Sep 6.
The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide that activates the antiviral response through the adaptor protein stimulator of interferon genes (STING). cGAMP cannot passively cross cell membranes, but recent advances have established a role for extracellular cGAMP as an "immunotransmitter" that can be imported into 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 signaling and that loss of ABCC1 reduced cGAMP export and potentiated STING signaling. We demonstrate that ABCC1 deficiency exacerbated cGAS-dependent autoimmunity in the Trex1 mouse model of Aicardi-Goutières syndrome. Thus, ABCC1-mediated cGAMP export is a key regulatory mechanism that limits cell-intrinsic activation of STING and ameliorates STING-dependent autoimmune disease.
DNA 传感器环鸟苷酸-腺苷酸合酶（cGAS）对于抗病毒和抗肿瘤免疫很重要。cGAS 生成可扩散的环二核苷酸环鸟苷酸-腺苷酸（cGAMP），通过干扰素基因刺激物（STING）衔接蛋白激活抗病毒反应。cGAMP 不能被动穿过细胞膜，但最近的进展确立了细胞外 cGAMP 作为“免疫递质”的作用，可以被导入细胞。然而，cGAMP 离开细胞的机制尚不清楚。在这里，我们鉴定出 ABCC1 是小鼠和人细胞中直接的、ATP 依赖性的 cGAMP 外排泵。我们表明，ABCC1 的过表达增强了 cGAMP 的外排，并限制了 STING 信号，而 ABCC1 的缺失减少了 cGAMP 的外排，并增强了 STING 信号。我们证明，ABCC1 缺陷使 Trex1 小鼠模型中的 Aicardi-Goutières 综合征中 cGAS 依赖性自身免疫恶化。因此，ABCC1 介导的 cGAMP 外排是限制 STING 细胞内激活的关键调节机制，并改善了 STING 依赖性自身免疫性疾病。
