Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France.
Nat Commun. 2023 Nov 1;14(1):6770. doi: 10.1038/s41467-023-42150-4.
Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.
I 型干扰素 (IFN) 信号受到严格调控。当环状 GMP-AMP 合酶 (cGAS) 识别 DNA 时，干扰素基因刺激物 (STING) 沿着内质网 (ER)-高尔基体轴易位，诱导 IFN 信号。通过自噬降解或通过逆行高尔基体到 ER 运输回收 STING 来实现终止。在这里，我们确定 GTP 酶 ADP-核糖基化因子 1 (ARF1) 是 cGAS-STING 信号的关键负调节剂。杂合 ARF1 错义突变导致以前未被识别的 I 型干扰素病，与增强的 IFN 刺激基因表达有关。与疾病相关的、GTPase 缺陷的 ARF1 增加细胞系和原代患者细胞中 cGAS-STING 依赖性 I 型 IFN 信号。在机制上，突变的 ARF1 破坏线粒体形态，通过异常的线粒体 DNA 释放导致 cGAS 激活，并由于逆行运输缺陷导致活跃的 STING 在高尔基体/ERGIC 处积累。我们的数据显示 ARF1 在维持 cGAS-STING 动态平衡方面具有意想不到的双重作用，通过促进线粒体完整性和 STING 回收。
