Department of Biochemistry, and Department of Thoracic Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Metabolic Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
EMBO J. 2023 Apr 17;42(8):e112387. doi: 10.15252/embj.2022112387. Epub 2023 Mar 6.
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.
cGAS-STING 通路通过感应病原体 DNA、诱导 I 型干扰素和启动自噬来发挥重要的宿主防御作用。然而，cGAS-STING 通路诱导的自噬中自噬体形成的分子机制尚不清楚。在这里，我们报告 STING 直接与 WIPI2 相互作用，WIPI2 是自噬中 LC3 脂质化的关键蛋白。与 WIPI2 的结合对于 STING 诱导的自噬体形成是必要的，但不影响 STING 的激活和细胞内运输。此外，STING 与 WIPI2 的 PI3P 结合基序的特异性相互作用导致 STING 与 PI3P 之间 WIPI2 结合的竞争，以及 STING 诱导的自噬和经典的 PI3P 依赖性自噬之间的相互抑制。此外，我们表明 STING-WIPI2 相互作用对于细胞质 DNA 的清除和 cGAS-STING 信号的衰减是必需的。因此，STING 与 WIPI2 的直接相互作用使 STING 能够绕过经典的上游机制来诱导 LC3 脂质化和自噬体形成。
