ATP2A2 regulates STING1/MITA-driven signal transduction including selective autophagy

作者：Xueli Yang, Linyue Lv, Yuelan Zhang, Zhuyou Zhang, Shaowei Zeng, Xinyi Zhang, Qinyang Wang, Martin E. Dorf, Shitao Li, Bishi Fu · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2496786 · 被引用次数：8 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Inflammasome and immune disorders

STING1/MITA not only induces innate immune responses but also triggers macroautophagy/autophagy to selectively degrade signaling molecules. However, the molecular mechanisms regulating STING1-mediated selective autophagy remain unclear. Here, we first report that ATP2A2 directly interacts with STING1, regulating STING1-mediated innate immune response by modulating its polymerization and trafficking, thereby inhibiting DNA virus infection. Notably, while screening for reticulophagy receptors involved in STING1-mediated selective autophagy, we identified SEC62 as an important receptor protein in STING1-mediated reticulophagy. Mechanistically, SEC62 strengthens its interaction with STING1 upon activation and concurrently facilitates STING1-mediated reticulophagy upon starvation, which are dependent on ATP2A2. Furthermore, knocking down SEC62 in WT cells inhibits STING1-mediated MAP1LC3B/LC3B lipidation and autophagosome formation, an effect that is lost in ATP2A2 knockout cells, suggesting that SEC62’s role in STING1-mediated selective autophagy is ATP2A2 dependent. Thus, our findings identify the reticulophagy receptor SEC62 as a novel receptor protein regulating STING1-mediated selective autophagy, providing new insight into the mechanism regarding a reticulophagy receptor in the process of STING1-induced selective autophagy.Abbrevations: aa: amino acids; AP-MS: affinity tag purification-mass spectrometry; ATP2A1: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; ...