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Deficiency in coatomer complex I causes aberrant activation of STING signalling

Author

Listed:
  • Annemarie Steiner

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Institute of Structural Biology, University Hospital Bonn)

  • Katja Hrovat-Schaale

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • 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
    University of Melbourne)

  • Pawat Laohamonthonkul

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Cassandra R. Harapas

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ronnie Ren Jie Low

    (University of Melbourne
    Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research)

  • Dominic Nardo

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    Monash Biomedicine Discovery Institute, Monash University)

  • Laura F. Dagley

    (University of Melbourne
    Advanced Technology and Biology, The Walter and Eliza Hall Institute of Medical Research)

  • 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
    Institute of Immunology, Philipps-University Marburg, BMFZ)

  • Gunther Hartmann

    (Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
    German Centre for Infection Research (DZIF), partner site Bonn-Cologne)

  • Michael P. Gantier

    (Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
    Monash University)

  • 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
    University of Genoa)

  • Sophia Davidson

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Seth L. Masters

    (Inflammation Division, The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • 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. Mlodzia, 2022. "Deficiency in coatomer complex I causes aberrant activation of STING signalling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29946-6
    DOI: 10.1038/s41467-022-29946-6
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    References listed on IDEAS

    as
    1. Xiang Gui & Hui Yang & Tuo Li & Xiaojun Tan & Peiqing Shi & Minghao Li & Fenghe Du & Zhijian J. Chen, 2019. "Autophagy induction via STING trafficking is a primordial function of the cGAS pathway," Nature, Nature, vol. 567(7747), pages 262-266, March.
    2. Kojiro Mukai & Emari Ogawa & Rei Uematsu & Yoshihiko Kuchitsu & Fumika Kiku & Takefumi Uemura & Satoshi Waguri & Takehiro Suzuki & Naoshi Dohmae & Hiroyuki Arai & Anthony K. Shum & Tomohiko Taguchi, 2021. "Homeostatic regulation of STING by retrograde membrane traffic to the ER," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    3. Hiroki Ishikawa & Zhe Ma & Glen N. Barber, 2009. "STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity," Nature, Nature, vol. 461(7265), pages 788-792, October.
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