Human STING is a proton channel

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.

Automated summary

The activation of STING leads to proton leakage from organelles, which triggers noncanonical lipidation of LC3B and inflammasome activation. Through structural analysis, it is suggested that STING functions as a proton channel. STING-induced proton flux in the Golgi and liposomes can be blocked by the STING agonist C53, leading to inhibition of LC3B lipidation and inflammasome activation. These findings demonstrate that the interferon-induction function of STING can be separated from its roles in LC3B lipidation and inflammasome activation.