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

Autor: Hirschenberger M; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany., Lepelley A; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France., Rupp U; Central Facility for Electron Microscopy, Ulm University, 89081, Ulm, Germany., Klute S; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany., Hunszinger V; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany., Koepke L; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany., Merold V; Institute of Virology, Technical University of Munich, 81675, Munich, Germany., Didry-Barca B; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France., Wondany F; Institute of Biophysics, Ulm University, 89081, Ulm, Germany., Bergner T; Central Facility for Electron Microscopy, Ulm University, 89081, Ulm, Germany., Moreau T; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France., Rodero MP; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France., Rösler R; Core Unit Mass Spectrometry and Proteomics, Ulm University, 89081, Ulm, Germany., Wiese S; Core Unit Mass Spectrometry and Proteomics, Ulm University, 89081, Ulm, Germany., Volpi S; UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Università degli Studi di Genova, Genoa, Italy., Gattorno M; UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Papa R; UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Lynch SA; Children's Health Ireland, Crumlin, Dublin, Eire.; University College Dublin, Dublin, Eire., Haug MG; Department of Medical Genetics, St. Olav's Hospital, Trondheim, Norway., Houge G; Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway., Wigby KM; Division of Genomic Medicine, Department of Pediatrics, University of California, Davis in Sacramento, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Sprague J; Division of Pediatric and Adolescent Dermatology, Rady Children's Hospital San Diego, San Diego, CA, USA.; Department of Dermatology, University of California San Diego School of Medicine, La Jolla, USA., Lenberg J; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Read C; Central Facility for Electron Microscopy, Ulm University, 89081, Ulm, Germany., Walther P; Central Facility for Electron Microscopy, Ulm University, 89081, Ulm, Germany., Michaelis J; Institute of Biophysics, Ulm University, 89081, Ulm, Germany., Kirchhoff F; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany., de Oliveira Mann CC; Institute of Virology, Technical University of Munich, 81675, Munich, Germany., Crow YJ; Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, F-75015, Paris, France. yanickcrow@mac.com.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. yanickcrow@mac.com., Sparrer KMJ; Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. Konstantin.Sparrer@uni-ulm.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 01; Vol. 14 (1), pp. 6770. Date of Electronic Publication: 2023 Nov 01.
DOI: 10.1038/s41467-023-42150-4
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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