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. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.
[doi:10.25345/C5X63B895]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: SILAC ; Quantitative Proteomics ; ARF1 ; Interferon ; STING ; cGAS ; Interferonopathy
Principal Investigators: (in alphabetical order) |
Dr. Konstantin Sparrer, Ulm University, Germany Dr. Sebastian Wiese, Ulm University, Deutschland |
Submitting User: | Wiese |
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