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Homeostatic regulation of STING by retrograde membrane traffic to the ER

Author

Listed:
  • Kojiro Mukai

    (Tohoku University)

  • Emari Ogawa

    (University of Tokyo)

  • Rei Uematsu

    (University of Tokyo)

  • Yoshihiko Kuchitsu

    (Tohoku University)

  • Fumika Kiku

    (University of Tokyo)

  • Takefumi Uemura

    (Fukushima Medical University School of Medicine)

  • Satoshi Waguri

    (Fukushima Medical University School of Medicine)

  • Takehiro Suzuki

    (RIKEN Center for Sustainable Resource Science)

  • Naoshi Dohmae

    (RIKEN Center for Sustainable Resource Science)

  • Hiroyuki Arai

    (University of Tokyo)

  • Anthony K. Shum

    (University of California San Francisco)

  • Tomohiko Taguchi

    (Tohoku University)

Abstract

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20234-9
    DOI: 10.1038/s41467-020-20234-9
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    Cited by:

    1. Haruka Kemmoku & Kanoko Takahashi & Kojiro Mukai & Toshiki Mori & Koichiro M. Hirosawa & Fumika Kiku & Yasunori Uchida & Yoshihiko Kuchitsu & Yu Nishioka & Masaaki Sawa & Takuma Kishimoto & Kazuma Tan, 2024. "Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. 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.
    3. Maximilian Hirschenberger & Alice Lepelley & Ulrich Rupp & Susanne Klute & Victoria Hunszinger & Lennart Koepke & Veronika Merold & Blaise Didry-Barca & Fanny Wondany & Tim Bergner & Tatiana Moreau & , 2023. "ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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