Human STING Enables Transmembrane Proton Transport

Stimulator of interferon genes (STING) carries out numerous biologic functions, including interferon induction, noncanonical LC3B lipidation, and NLRP3 inflammasome activation. The mechanisms that underlie STING-mediated interferon induction have been well established, but the mechanisms that lead to STING's activation of noninterferon functions have not been fully elucidated. As studies have shown that organelle proton leakage can signal for LC3B lipidation and inflammasome activation, Liu, Carlson, and colleagues sought to determine if organelle proton leakage is also involved in STING-induced LC3B lipidation and, if so, how STING activation affects this ion transport. Results revealed that activation of STING increased the pH in the Golgi, and evaluation of genes that mediate this increase in pH indicated that no known transporters mediate STING-induced LC3B lipidation, but the transmembrane domain of STING was demonstrated to have an important role in LC3B lipidation upon STING translocation. Analysis of published cryo-electron microscopy structures of chicken STING suggested that STING bound to ligand created a pore spanning the lipid bilayer, and use of the STING agonist compound 53 (C53), which binds to the STING transmembrane domain in the area of the pore, reduced the STING-mediated increase in pH of the Golgi. Purification of full-length human STING and its reconstitution into liposomes revealed proton flux in STING proteoliposomes that could also be reduced upon C53 treatment, supporting that STING is sufficient to transport proton across lipid membranes. Moreover, the channel activity of STING was found to be required for the induction of LC3B lipidation as well as for NLRP3 inflammasome activation. In summary, the results of this study show that human STING functions as a proton channel to induce LC3B lipidation and NLRP3 inflammasome activation, which together, suggest that decoupling of STING phosphorylation from these processes is possible.

Liu B, Carlson RJ, Pires IS, Gentili M, Feng E, Hellier Q, et al. Human STING is a proton channel. Science 2023;381:508–14.

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