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

Autor:	Xun J; Xiangya School of Medicine, Central South University, Changsha, China.; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Zhang Z; College of Life Sciences, Shanxi Agricultural University, Taiyuan, China., Lv B; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Lu D; College of Life Sciences, Shanxi Agricultural University, Taiyuan, China., Yang H; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Shang G; College of Life Sciences, Shanxi Agricultural University, Taiyuan, China. gjshang@gmail.com.; The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China. gjshang@gmail.com.; Shanxi Provincial Key Laboratory of Protein Structure Determination, SAARI, Taiyuan, China. gjshang@gmail.com., Tan JX; Aging Institute, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Jay.Tan@pitt.edu.; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Jay.Tan@pitt.edu.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2024 Feb; Vol. 25 (2), pp. 544-569. Date of Electronic Publication: 2024 Jan 02.
DOI:	10.1038/s44319-023-00045-x
Abstrakt:	The cGAS/STING pathway triggers inflammation upon diverse cellular stresses such as infection, cellular damage, aging, and diseases. STING also triggers noncanonical 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 deacidification in other contexts, it is unclear how STING activates V-ATPase for noncanonical autophagy. Here we report a conserved channel function of STING in proton efflux and vesicle deacidification. STING activation induces an electron-sparse pore in its transmembrane domain, which mediates proton flux in vitro and the deacidification 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 deacidification, LC3 lipidation, and cell death, without affecting trafficking. The discovery of STING as a channel opens new opportunities for selective targeting of canonical and noncanonical STING functions. (© 2024. The Author(s).)
Databáze:	MEDLINE
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