| First Author | Tu X | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 6977 |
| PubMed ID | 36379959 | Mgi Jnum | J:346915 |
| Mgi Id | MGI:7386238 | Doi | 10.1038/s41467-022-33765-0 |
| Citation | Tu X, et al. (2022) Interruption of post-Golgi STING trafficking activates tonic interferon signaling. Nat Commun 13(1):6977 |
| abstractText | 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. |
