Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Cell Biol. 2022 Jul 4;221(7). doi: 10.1083/jcb.202202060. Epub 2022 May 5.
The stimulator of interferon genes (STING) plays a critical role in innate immunity. Emerging evidence suggests that STING is important for DNA or cGAMP-induced non-canonical autophagy, which is independent of a large part of canonical autophagy machineries. Here, we report that, in the absence of STING, energy stress-induced autophagy is upregulated rather than downregulated. Depletion of STING in Drosophila fat cells enhances basal- and starvation-induced autophagic flux. During acute exercise, STING knockout mice show increased autophagy flux, exercise endurance, and altered glucose metabolism. Mechanistically, these observations could be explained by the STING-STX17 interaction. STING physically interacts with STX17, a SNARE that is essential for autophagosome biogenesis and autophagosome-lysosome fusion. Energy crisis and TBK1-mediated phosphorylation both disrupt the STING-STX17 interaction, allow different pools of STX17 to translocate to phagophores and mature autophagosomes, and promote autophagic flux. Taken together, we demonstrate a heretofore unexpected function of STING in energy stress-induced autophagy through spatial regulation of autophagic SNARE STX17.
干扰素基因刺激物 (STING) 在先天免疫中发挥着关键作用。新出现的证据表明，STING 对于 DNA 或 cGAMP 诱导的非典型自噬很重要，而这种自噬不依赖于大部分典型的自噬机制。在这里，我们报告说，在没有 STING 的情况下，能量应激诱导的自噬会被上调，而不是下调。在果蝇脂肪细胞中耗尽 STING 会增强基础饥饿诱导的自噬通量。在急性运动期间，STING 敲除小鼠表现出增加的自噬通量、运动耐力和改变的葡萄糖代谢。从机制上讲，这些观察结果可以用 STING-STX17 相互作用来解释。STING 与 STX17 发生物理相互作用，STX17 是自噬体生物发生和自噬体-溶酶体融合所必需的 SNARE。能量危机和 TBK1 介导的磷酸化都会破坏 STING-STX17 相互作用，允许不同池的 STX17 易位到吞噬体和成熟的自噬体，并促进自噬通量。总之，我们通过对自噬 SNARE STX17 的空间调节，证明了 STING 在能量应激诱导的自噬中的一个迄今为止未被发现的功能。
