Deficiency in coatomer complex I causes aberrant activation of STING signalling

Annemarie Steiner, Katja Hrovat-Schaale, Ignazia Prigione, Chien-Hsiung Yu, Pawat Laohamonthonkul, Cassandra R. Harapas, Ronnie Ren Jie Low, Dominic Nardo, Laura F. Dagley, Michael J. Mlodzianoski, Kelly L. Rogers, Thomas Zillinger, Gunther Hartmann, Michael P. Gantier, Marco Gattorno, Matthias Geyer, Stefano Volpi, Sophia Davidson and Seth L. Masters ()
Additional contact information
Annemarie Steiner: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Katja Hrovat-Schaale: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Ignazia Prigione: Centre for Autoinflammatory Diseases and Primary Immunodeficiencies, IRCCS Istituto Giannina Gaslini
Chien-Hsiung Yu: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Pawat Laohamonthonkul: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Cassandra R. Harapas: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Ronnie Ren Jie Low: University of Melbourne
Dominic Nardo: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Laura F. Dagley: University of Melbourne
Michael J. Mlodzianoski: Center for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research
Kelly L. Rogers: Center for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research
Thomas Zillinger: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Gunther Hartmann: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Michael P. Gantier: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
Marco Gattorno: Centre for Autoinflammatory Diseases and Primary Immunodeficiencies, IRCCS Istituto Giannina Gaslini
Matthias Geyer: Institute of Structural Biology, University Hospital Bonn
Stefano Volpi: Centre for Autoinflammatory Diseases and Primary Immunodeficiencies, IRCCS Istituto Giannina Gaslini
Sophia Davidson: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
Seth L. Masters: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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 associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.

Date: 2022
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DOI: 10.1038/s41467-022-29946-6

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