Liu and Carlson et al. studied mechanisms underlying STING induction of non-IFN functions. STING activation increased the Golgi pH. LC3B lipidation upon STING ER to Golgi translocation was not due to known channel proteins that mediate proton flux, and required STING’s TM domain, which analysis of Cryo-EM structure showed included a pore that spanned the lipid bilayer of ligand-bound, but not free chicken STING. Full-length human STING reconstituted into liposomes enabled TM proton transport. C53, a STING agonist that binds its TM in the area of the pore, inhibited STING-induced proton flux in the Golgi, LC3B lipidation, NLRP3 inflammasome activation, and IL-1β release.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Broad Institute, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. The Koch Institute for Integrative Cancer Research at MIT
Author Info: (1) Broad Institute, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA. (2) Broad Institute, Cambridge, MA, USA. Massachusetts Institute of Technology, Department of Health Sciences and Technology, Cambridge, MA, USA. (3) The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA. (4) Broad Institute, Cambridge, MA, USA. (5) Broad Institute, Cambridge, MA, USA. Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA. (6) Broad Institute, Cambridge, MA, USA. (7) Broad Institute, Cambridge, MA, USA. Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Broad Institute, Cambridge, MA, USA. The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA. Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA. (9) The Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA. (10) Broad Institute, Cambridge, MA, USA. Massachusetts General Hospital Cancer Center, Boston, MA, USA.
