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Deficiency in coatomer complex I causes aberrant activation of STING signalling.

Nature communications

Authors: Annemarie Steiner, Katja Hrovat-Schaale, Ignazia Prigione, Chien-Hsiung Yu, Pawat Laohamonthonkul, Cassandra R Harapas, Ronnie Ren Jie Low, Dominic De 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, Seth L Masters

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.

© 2022. The Author(s).

PMID: 35484149

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