ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling

ABSTRACT 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 ARF1 as a crucial negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene expression. Disease-associated, GTPase-defective, ARF1 results in increased cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial fusion causing cGAS activation by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show that ARF1 has an unexpected dual role in maintaining cGAS-STING homeostasis, through the promotion of mitochondrial fusion and STING recycling.