Human STING is a proton channel
- Science. 2023 Aug 4;381(6657):508-514. doi: 10.1126/science.adf8974.
- 1. Broad Institute, Cambridge, MA, USA.
- 2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
- 3. The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
- 4. Massachusetts Institute of Technology, Department of Health Sciences and Technology, Cambridge, MA, USA.
- 5. Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA.
- 6. Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
- 7. Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA.
- 8. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- 9. Massachusetts General Hospital Cancer Center, Boston, MA, USA.
- # Contributed equally.
Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of interferon genes (STING) activation. On the basis of structural analysis, we hypothesized that human STING is a proton channel. Indeed, we found that STING activation induced a pH increase in the Golgi and that STING reconstituted in liposomes enabled transmembrane proton transport. Compound 53 (C53), a STING agonist that binds the putative channel interface, blocked STING-induced proton flux in the Golgi and in liposomes. STING-induced LC3B lipidation and inflammasome activation were also inhibited by C53, suggesting that STING's channel activity is critical for these two processes. Thus, STING's interferon-induction function can be decoupled from its roles in LC3B lipidation and inflammasome activation.