STING directly recruits WIPI2 for autophagosome formation during STING‐induced autophagy
STING directly recruits WIPI2 for autophagosome formation during STING‐induced autophagy
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DOI：
10.15252/embj.2022112387
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
W. Wan;Chuying Qian;Qian Wang;Jin Li;Hongtao Zhang;Lei Wang;Maomao Pu;Yewei Huang;Zhengfu He;Tianhua Zhou;Han-Ming Shen;W. Liu
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文献类型：
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作者：
W. Wan;Chuying Qian;Qian Wang;Jin Li;Hongtao Zhang;Lei Wang;Maomao Pu;Yewei Huang;Zhengfu He;Tianhua Zhou;Han-Ming Shen;W. Liu
cGAS-STING途径通过感应病原体DNA、诱导I型IFN和启动自噬在宿主防御中起重要作用。然而，在cGAS-STING途径诱导的自噬中自噬体形成的分子机制仍不清楚。在这里，我们报告STING直接与WIPI 2相互作用，WIPI 2是自噬中LC 3脂化的关键蛋白。与WIPI 2的结合是STING诱导的自噬体形成所必需的，但不影响STING活化和细胞内运输。此外，STING和WIPI 2的PI 3 P结合基序之间的特异性相互作用导致STING和PI 3 P之间竞争WIPI 2结合，以及STING诱导的自噬和典型的PI 3 P依赖性自噬之间的相互抑制。此外，我们表明STING-WIPI 2相互作用是清除细胞质DNA和减弱cGAS-STING信号传导所必需的。因此，STING和WIPI 2之间的直接相互作用使得STING能够绕过典型的上游机制以诱导LC 3脂化和自噬体形成。
The cGAS‐STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS‐STING pathway‐induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING‐induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P‐binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING‐induced autophagy and canonical PI3P‐dependent autophagy. Furthermore, we show that the STING‐WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS‐STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.