TY  - JOUR
AU  - Lang, Johannes
AU  - Bergner, Tim
AU  - Zinngrebe, Julia
AU  - Lepelley, Alice
AU  - Vill, Katharina
AU  - Leiz, Steffen
AU  - Wlaschek, Meinhard
AU  - Wagner, Matias
AU  - Scharffetter-Kochanek, Karin
AU  - Fischer-Posovszky, Pamela
AU  - Read, Clarissa
AU  - Crow, Yanick J
AU  - Hirschenberger, Maximilian
AU  - Sparrer, Konstantin M J
TI  - Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.
JO  - EMBO reports
VL  - 26
IS  - 9
SN  - 1469-221X
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-00606
SP  - 2232 - 2261
PY  - 2025
AB  - 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 signalling. We identify a de novo heterozygous s.55 C > T/p.R19C ARF1 variant in a patient with type I interferonopathy symptoms. The GTPase-deficient variant ARF1 R19C selectively disrupts COPI binding and retrograde transport of STING, thereby prolonging innate immune activation without affecting mitochondrial integrity. Treatment of patient fibroblasts in vitro with the STING signalling inhibitors H-151 and amlexanox reduces chronic interferon signalling. Summarizing, our data reveal the molecular basis of a ARF1-associated type I interferonopathy allowing dissection of the two roles of ARF1, and suggest that pharmacological targeting of STING may alleviate ARF1-associated auto-inflammation.
KW  - Humans
KW  - Nucleotidyltransferases: metabolism
KW  - Nucleotidyltransferases: genetics
KW  - ADP-Ribosylation Factor 1: genetics
KW  - ADP-Ribosylation Factor 1: metabolism
KW  - Signal Transduction
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Mutation
KW  - Fibroblasts: metabolism
KW  - Interferon Type I: metabolism
KW  - Mitochondria: metabolism
KW  - HEK293 Cells
KW  - ARF1 (Other)
KW  - Interferon (Other)
KW  - Interferonopathy (Other)
KW  - STING (Other)
KW  - cGAS (Other)
KW  - STING1 protein, human (NLM Chemicals)
KW  - Nucleotidyltransferases (NLM Chemicals)
KW  - ADP-Ribosylation Factor 1 (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - cGAS protein, human (NLM Chemicals)
KW  - ARF1 protein, human (NLM Chemicals)
KW  - Interferon Type I (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40128408
C2  - pmc:PMC7617634
DO  - DOI:10.1038/s44319-025-00423-7
UR  - https://pub.dzne.de/record/278573
ER  -