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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 6770 (11 01 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37914730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Springer Nature Limited.

Chemical References

• ADP-Ribosylation Factor 1
• Interferon Type I
• Membrane Proteins
• Nucleotidyltransferases
• STING1 protein, human
• ARF1 protein, human

Topics

• Humans
• ADP-Ribosylation Factor 1 (genetics, metabolism)
• Interferon Type I (metabolism)
• Membrane Proteins (metabolism)
• Nucleotidyltransferases (genetics, metabolism)
• Signal Transduction