Nature Communications (Nov 2023)
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. de Oliveira Mann,
- Yanick J. Crow,
- Konstantin M. J. Sparrer
Affiliations
- Maximilian Hirschenberger
- Institute of Molecular Virology, Ulm University Medical Center
- Alice Lepelley
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
- Ulrich Rupp
- Central Facility for Electron Microscopy, Ulm University
- Susanne Klute
- Institute of Molecular Virology, Ulm University Medical Center
- Victoria Hunszinger
- Institute of Molecular Virology, Ulm University Medical Center
- Lennart Koepke
- Institute of Molecular Virology, Ulm University Medical Center
- Veronika Merold
- Institute of Virology, Technical University of Munich
- Blaise Didry-Barca
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
- Fanny Wondany
- Institute of Biophysics, Ulm University
- Tim Bergner
- Central Facility for Electron Microscopy, 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
- Core Unit Mass Spectrometry and Proteomics, Ulm University
- Sebastian Wiese
- Core Unit Mass Spectrometry and Proteomics, Ulm University
- Stefano Volpi
- UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini
- Marco Gattorno
- UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini
- Riccardo Papa
- UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini
- Sally-Ann Lynch
- Children’s Health Ireland, Crumlin
- Marte G. Haug
- Department of Medical Genetics, St. Olav’s Hospital
- Gunnar Houge
- Department of Medical Genetics, Haukeland University Hospital
- Kristen M. Wigby
- Division of Genomic Medicine, Department of Pediatrics, University of California
- Jessica Sprague
- Division of Pediatric and Adolescent Dermatology, Rady Children’s Hospital San Diego
- Jerica Lenberg
- Rady Children’s Institute for Genomic Medicine
- Clarissa Read
- Central Facility for Electron Microscopy, Ulm University
- Paul Walther
- Central Facility for Electron Microscopy, Ulm University
- Jens Michaelis
- Institute of Biophysics, Ulm University
- Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center
- Carina C. de Oliveira Mann
- Institute of Virology, Technical University of Munich
- Yanick J. Crow
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163
- Konstantin M. J. Sparrer
- Institute of Molecular Virology, Ulm University Medical Center
- DOI
- https://doi.org/10.1038/s41467-023-42150-4
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
