MassIVE MSV000089711

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

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Description

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

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Principal Investigators:
(in alphabetical order) 		Dr. Konstantin Sparrer, Ulm University, Germany
Dr. Sebastian Wiese, Ulm University, Deutschland
Submitting User: Wiese
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