Deficiency in coatomer complex I causes aberrant activation of STING signalling

A Steiner; K Hrovat-Schaale; I Prigione; CH Yu; P Laohamonthonkul; CR Harapas; RRJ Low; D De Nardo; LF Dagley; MJ Mlodzianoski; KL Rogers; T Zillinger; G Hartmann; MP Gantier; M Gattorno; M Geyer; S Volpi; S Davidson; SL Masters

Journal article

Deficiency in coatomer complex I causes aberrant activation of STING signalling

A Steiner, K Hrovat-Schaale, I Prigione, CH Yu, P Laohamonthonkul, CR Harapas, RRJ Low, D De Nardo, LF Dagley, MJ Mlodzianoski, KL Rogers, T Zillinger, G Hartmann, MP Gantier, M Gattorno, M Geyer, S Volpi, S Davidson, SL Masters

Nature Communications | NATURE PORTFOLIO | Published : 2022

DOI: 10.1038/s41467-022-29946-6

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Abstract

Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associ..

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University of Melbourne Researchers

Annemarie Steiner Author

Michael Mlodzianoski Author

Kelly Rogers Author

Seth Masters Author

Grants

Awarded by Institute for Frontier Materials, Deakin University

Funding Acknowledgements

This work was supported by: Fellowships from the Australian National Health and Medical Research Council (NHMRC GNT2008699) (S.L.M.), HHMI-Wellcome International Research Scholarship 208694/Z/17/Z (S.L.M.), the Sylvia and Charles Viertel Foundation VTL2016F027 (S.L.M.), the National Health and Medical Research Council Early Career Fellowship (S.D. GNT1143412), the WEHI Centenary Fellowship (C.-H.Y.) and Ormond College's Thwaites Gutch Fellowship in Physiology (C.-H.Y.), Italian Ministry of Health, Ricerca Corrente (M.Ga.). M,Ge., G.H. and T.Z. received funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy -EXC2151 -390873048 and TRR237 (G.H., T.Z.). A.S. is supported by the University of Melbourne through the International Research Training Program Scholarship and the DFG -GRK 2168. S.L.M. receives funding from Glaxosmithkline and IFM therapeutics. S.V. received financial support from the Italian Ministry of Foreign Affairs/Italian Health Ministry (PGR grant IN17GR10).