ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Maximilian Hirschenberger
,
Alice Lepelley
(1)
,
Ulrich Rupp
,
Susanne Klute
,
Victoria Hunszinger
,
Lennart Koepke
(2)
,
Veronika Merold
,
Blaise Didry-Barca
,
Fanny Wondany
,
Tim Bergner
,
Tatiana Moreau
,
Mathieu Rodero
(3)
,
Reinhild Rösler
,
Sebastian Wiese
,
Stefano Volpi
(4)
,
Marco Gattorno
(5)
,
Riccardo Papa
(6)
,
Sally-Ann Lynch
,
Marte Haug
,
Gunnar Houge
(7)
,
Kristen Wigby
,
Jessica Sprague
,
Jerica Lenberg
,
Clarissa Read
,
Paul Walther
,
Jens Michaelis
,
Frank Kirchhoff
,
Carina de Oliveira Mann
,
Yanick Crow
,
Konstantin Sparrer
1
Equipe Inserm U1163 -
Laboratory of neurogenetics and neuroinflammation
2 UUlm - University of Ulm
3 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
4 Dipartimento di Scienze Chimiche,della Vita e della Sostenibilità Ambientale
5 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
6 Istituto Giannina Gaslini, Genova
7 Haukeland University Hospital
2 UUlm - University of Ulm
3 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
4 Dipartimento di Scienze Chimiche,della Vita e della Sostenibilità Ambientale
5 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
6 Istituto Giannina Gaslini, Genova
7 Haukeland University Hospital
Maximilian Hirschenberger
- Function : Author
Alice Lepelley
- Function : Author
- PersonId : 762742
- ORCID : 0000-0001-8656-7291
Ulrich Rupp
- Function : Author
Susanne Klute
- Function : Author
Victoria Hunszinger
- Function : Author
- PersonId : 1304092
- ORCID : 0009-0004-6048-549X
Veronika Merold
- Function : Author
Blaise Didry-Barca
- Function : Author
Fanny Wondany
- Function : Author
Tim Bergner
- Function : Author
Tatiana Moreau
- Function : Author
Reinhild Rösler
- Function : Author
Sebastian Wiese
- Function : Author
- PersonId : 1304094
- ORCID : 0000-0001-5697-2608
Riccardo Papa
- Function : Author
- PersonId : 798856
- ORCID : 0000-0002-9626-5470
Sally-Ann Lynch
- Function : Author
- PersonId : 1304095
- ORCID : 0000-0003-3540-1333
Marte Haug
- Function : Author
Kristen Wigby
- Function : Author
Jessica Sprague
- Function : Author
Jerica Lenberg
- Function : Author
Clarissa Read
- Function : Author
- PersonId : 1304096
- ORCID : 0000-0002-4632-2684
Paul Walther
- Function : Author
Jens Michaelis
- Function : Author
- PersonId : 1260096
- ORCID : 0000-0002-2739-4172
Frank Kirchhoff
- Function : Author
- PersonId : 1304097
- ORCID : 0000-0002-7052-2360
Carina de Oliveira Mann
- Function : Author
- PersonId : 1304098
- ORCID : 0000-0002-1852-9880
Yanick Crow
- Function : Author
- PersonId : 11918
- IdHAL : yanick-crow
- ORCID : 0000-0001-7211-7564
- IdRef : 227205359
Konstantin Sparrer
- Function : Author
- PersonId : 1304099
- ORCID : 0000-0002-8682-1779
Abstract
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 ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.