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A conserved ion channel function of STING mediates non-canonical autophagy and cell death

ABSTRACT: The cGAS/STING pathway triggers inflammation upon diverse cellular stresses such as infection, cellular damage, aging, and diseases. STING also triggers non-canonical autophagy, involving LC3 lipidation on STING vesicles through the V-ATPase-ATG16L1 axis, as well as induces cell death. Although the proton pump V-ATPase senses organelle de-acidification in other contexts, it is unclear how STING activates V-ATPase for non-canonical autophagy. Here we report a conserved channel function of STING in proton efflux and vesicle de-acidification. STING activation induces an electron-sparse pore in its transmembrane domain, which mediates proton flux in vitro and the de-acidification of post-Golgi STING vesicles in cells. A chemical ligand of STING, C53, which binds to and blocks its channel, strongly inhibits STING-mediated proton flux in vitro. C53 fully blocks STING trafficking from the ER to the Golgi, but adding C53 after STING arrives at the Golgi allows for selective inhibition of STING-dependent vesicle de-acidification, LC3 lipidation, and cell death, without affecting trafficking. The discovery of STING as a channel opens new opportunities for selective targeting of canonical and non-canonical STING functions.

SUBMITTER: Jinrui Xun

PROVIDER: S-SCDT-10_1038-S44319-023-00045-X | biostudies-other |

REPOSITORIES: biostudies-other

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A conserved ion channel function of STING mediates noncanonical autophagy and cell death.

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