TY - JOUR
T1 - Interruption of post-Golgi STING trafficking activates tonic interferon signaling
AU - Tu, Xintao
AU - Chu, Ting Ting
AU - Jeltema, Devon
AU - Abbott, Kennady
AU - Yang, Kun
AU - Xing, Cong
AU - Han, Jie
AU - Dobbs, Nicole
AU - Yan, Nan
N1 - Funding Information:
We thank Yang-Xin Fu and members of the Fu lab for advice on tumor experiments, Robert Hammer and Mylinh Nguyen at the UTSW Transgenic Technology Center, Kate Phelps and Abhijit Bugde at the UT Southwestern Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, supported in part by NCI Cancer Center Support Grant 1P30 CA142543-01, NIH Shared Instrumentation Award 1S10 OD021684-01, members of the Yan lab for discussions. This work was also supported by National Institutes of Health (AI151708, NS117424, NS122825 to N.Y.), Cancer Prevention and Research Institute of Texas (CPRIT, RP180288, RP220242 to N.Y.), the Burroughs Wellcome Fund (N.Y.), UT Southwestern Immunology T32 training grant (5T32AI005284, to K.A. and D.J.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33765-0
DO - 10.1038/s41467-022-33765-0
M3 - Article
C2 - 36379959
AN - SCOPUS:85141998655
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6977
ER -