Interruption of post-Golgi STING trafficking activates tonic interferon signaling

Xintao Tu, Ting-Ting Chu, Devon Jeltema, Kennady Abbott, Kun Yang, Cong Xing, Jie Han, Nicole Dobbs and Nan Yan ()
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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

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

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33765-0

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