2025-03-18 ワシントン大学セントルイス校
<関連情報>
- https://source.washu.edu/2025/03/researchers-find-missing-link-in-autoimmune-disorder/
- https://medicine.washu.edu/news/researchers-find-missing-link-in-autoimmune-disorder/
- https://www.cell.com/cell/abstract/S0092-8674(25)00096-0
ArfGAP2はSTINGプロトンチャネル活性、サイトカイン通過、自己炎症を促進する ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation
Subhajit Poddar∙ Samuel D. Chauvin∙ Christopher H. Archer∙ … ∙ Sumit K. Chanda∙ David J. Kast∙ Jonathan J. Miner
Cell Published:February 12, 2025
DOI:https://doi.org/10.1016/j.cell.2025.01.027
Graphical abstract
Highlights
- STING proton channel activity regulates Golgi trafficking of cytokine cargos
- ArfGAP2 facilitates STING-mediated proton efflux and cytokine trafficking
- Deletion of ArfGAP2 ameliorates STING-associated autoinflammation in mice
Summary
Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
