ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
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Published:2023-11-01
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hirschenberger Maximilian, Lepelley AliceORCID, Rupp Ulrich, Klute Susanne, Hunszinger VictoriaORCID, Koepke LennartORCID, Merold Veronika, Didry-Barca Blaise, Wondany Fanny, Bergner Tim, Moreau Tatiana, Rodero Mathieu P., Rösler Reinhild, Wiese SebastianORCID, Volpi Stefano, Gattorno Marco, Papa RiccardoORCID, Lynch Sally-AnnORCID, Haug Marte G., Houge Gunnar, Wigby Kristen M., Sprague Jessica, Lenberg Jerica, Read ClarissaORCID, Walther Paul, Michaelis JensORCID, Kirchhoff FrankORCID, de Oliveira Mann Carina C.ORCID, Crow Yanick J.ORCID, Sparrer Konstantin M. J.ORCID
Abstract
AbstractType 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference83 articles.
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