TY - JOUR
T1 - ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
AU - Hirschenberger, Maximilian
AU - Lepelley, Alice
AU - Rupp, Ulrich
AU - Klute, Susanne
AU - Hunszinger, Victoria
AU - Koepke, Lennart
AU - Merold, Veronika
AU - Didry-Barca, Blaise
AU - Wondany, Fanny
AU - Bergner, Tim
AU - Moreau, Tatiana
AU - Rodero, Mathieu P.
AU - Rösler, Reinhild
AU - Wiese, Sebastian
AU - Volpi, Stefano
AU - Gattorno, Marco
AU - Papa, Riccardo
AU - Lynch, Sally Ann
AU - Haug, Marte G.
AU - Houge, Gunnar
AU - Wigby, Kristen M.
AU - Sprague, Jessica
AU - Lenberg, Jerica
AU - Read, Clarissa
AU - Walther, Paul
AU - Michaelis, Jens
AU - Kirchhoff, Frank
AU - de Oliveira Mann, Carina C.
AU - Crow, Yanick J.
AU - Sparrer, Konstantin M.J.
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85175699232&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-42150-4
DO - 10.1038/s41467-023-42150-4
M3 - Article
C2 - 37914730
AN - SCOPUS:85175699232
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6770
ER -