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Interruption of post-Golgi STING trafficking activates tonic interferon signaling

Author

Listed:
  • Xintao Tu

    (UT Southwestern Medical Center)

  • Ting-Ting Chu

    (UT Southwestern Medical Center)

  • Devon Jeltema

    (UT Southwestern Medical Center)

  • Kennady Abbott

    (UT Southwestern Medical Center)

  • Kun Yang

    (UT Southwestern Medical Center)

  • Cong Xing

    (UT Southwestern Medical Center)

  • Jie Han

    (UT Southwestern Medical Center)

  • Nicole Dobbs

    (UT Southwestern Medical Center)

  • Nan Yan

    (UT Southwestern Medical Center
    UT Southwestern Medical Center)

Abstract

Activation of the cGAS-STING pathway is traditionally considered a “trigger-release” mechanism where detection of microbial DNA or cyclic di-nucleotides sets off the type I interferon response. Whether this pathway can be activated without pathogenic ligand exposure is less well understood. Here we show that loss of Golgi-to-lysosome STING cofactors, but not ER-to-Golgi cofactors, selectively activates tonic interferon signalling. Impairment of post-Golgi trafficking extends STING Golgi-dwell time, resulting in elevated immune signalling and protection against infection. Mechanistically, trans-Golgi coiled coil protein GCC2 and several RAB GTPases act as key regulators of STING post-Golgi trafficking. Genomic deletion of these factors potently activates cGAS-STING signalling without instigating any pathogenic trigger for cGAS. Gcc2−/− mice develop STING-dependent serologic autoimmunity. Gcc2-deleted or Rab14-deleted cancer cells induce T-cell and IFN-dependent anti-tumour immunity and inhibit tumour growth in mice. In summary, we present a “basal flux” mechanism for tonic cGAS-STING signalling, regulated at the level of post-Golgi STING trafficking, which could be exploited for cancer immunotherapy.

Suggested Citation

  • Xintao Tu & Ting-Ting Chu & Devon Jeltema & Kennady Abbott & Kun Yang & Cong Xing & Jie Han & Nicole Dobbs & Nan Yan, 2022. "Interruption of post-Golgi STING trafficking activates tonic interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33765-0
    DOI: 10.1038/s41467-022-33765-0
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    References listed on IDEAS

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