Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signaling

ABSTRACT: Tight control of cGAS-STING mediated DNA sensing is crucial to avoid auto-inflammation. The GTPase ADP-ribosylation factor 1 (ARF1) is crucial to maintain cGAS-STING homeostasis and various pathogenic ARF1 variants are associated with type I interferonopathies. Functional ARF1 inhibits STING activity by maintaining mitochondrial integrity and facilitating COPI-mediated retrograde STING trafficking and deactivation. Yet the factors governing the two distinct functions of ARF1 remained unexplored. Here, we dissect ARF1's dual role by a comparative analysis of disease-associated ARF1 variants and their impact on STING signaling. We identify a de novo heterozygous s.55C>T/p.R19C ARF1 variant in a patient with type I interferonopathy symptoms. The GTPase-deficient variant ARF1 R19C selective

SUBMITTER: Johannes Lang 

PROVIDER: S-SCDT-10_1038-S44319-025-00423-7 | biostudies-other |

REPOSITORIES: biostudies-other