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

Maximilian Hirschenberger, Alice Lepelley, Ulrich Rupp, Susanne Klute, Victoria Hunszinger, Lennart Koepke, Veronika Merold, Blaise Didry-Barca, Fanny Wondany, Tim Bergner, Tatiana Moreau, Mathieu P. Rodero, Reinhild Rösler, Sebastian Wiese, Stefano Volpi, Marco Gattorno, Riccardo Papa, Sally-Ann Lynch, Marte G. Haug, Gunnar Houge, Kristen M. Wigby, Jessica Sprague, Jerica Lenberg, Clarissa Read, Paul Walther, Jens Michaelis, Frank Kirchhoff, Carina C. Oliveira Mann, Yanick J. Crow () and Konstantin M. J. Sparrer ()
Additional contact information
Maximilian Hirschenberger: Ulm University Medical Center
Alice Lepelley: Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
Ulrich Rupp: Ulm University
Susanne Klute: Ulm University Medical Center
Victoria Hunszinger: Ulm University Medical Center
Lennart Koepke: Ulm University Medical Center
Veronika Merold: Technical University of Munich
Blaise Didry-Barca: Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
Fanny Wondany: Ulm University
Tim Bergner: Ulm University
Tatiana Moreau: Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
Mathieu P. Rodero: Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
Reinhild Rösler: Ulm University
Sebastian Wiese: Ulm University
Stefano Volpi: IRCCS Istituto Giannina Gaslini
Marco Gattorno: IRCCS Istituto Giannina Gaslini
Riccardo Papa: IRCCS Istituto Giannina Gaslini
Sally-Ann Lynch: Children’s Health Ireland, Crumlin
Marte G. Haug: St. Olav’s Hospital
Gunnar Houge: Haukeland University Hospital
Kristen M. Wigby: University of California
Jessica Sprague: Rady Children’s Hospital San Diego
Jerica Lenberg: Rady Children’s Institute for Genomic Medicine
Clarissa Read: Ulm University
Paul Walther: Ulm University
Jens Michaelis: Ulm University
Frank Kirchhoff: Ulm University Medical Center
Carina C. Oliveira Mann: Technical University of Munich
Yanick J. Crow: Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
Konstantin M. J. Sparrer: Ulm University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42150-4

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DOI: 10.1038/s41467-023-42150-4

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