A conserved ion channel function of STING mediates noncanonical autophagy and cell death.
A conserved ion channel function of STING mediates noncanonical autophagy and cell death.
复制标题
STING 的保守离子通道功能介导非典型自噬和细胞死亡。
DOI：
10.1038/s44319-023-00045-x
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发表时间：
2024
期刊：
影响因子：
7.7
通讯作者：
Tan,JayXiaojun
中科院分区：
文献类型：
--
作者：
Xun,Jinrui;Zhang,Zhichao;Lv,Bo;Lu,Defen;Yang,Haoxiang;Shang,Guijun;Tan,JayXiaojun
cGAS/STING通路在不同的细胞应激（例如感染、细胞损伤、衰老和疾病）时触发炎症。STING还触发非典型的自噬，涉及通过V-ATP酶-ATG 16 L1轴在STING囊泡上的LC 3脂化，以及诱导细胞死亡。虽然质子泵V-ATP酶在其他情况下感知细胞器脱酸，但目前尚不清楚STING如何激活V-ATP酶进行非经典自噬。在这里，我们报告一个保守的通道功能的STING质子流出和囊泡脱酸。STING激活在其跨膜结构域中诱导电子稀疏孔，其介导体外质子通量和细胞中高尔基体后STING囊泡的脱酸。STING的化学配体C53结合并阻断其通道，在体外强烈抑制STING介导的质子通量。C53完全阻断STING从ER到高尔基体的运输，但在STING到达高尔基体后添加C53允许选择性抑制STING依赖性囊泡脱酸、LC 3脂化和细胞死亡，而不影响运输。STING作为通道的发现为选择性靶向经典和非经典STING功能开辟了新的机会。
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.