TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling

The CGAS-STING1 pathway plays a key role in detecting cytosolic DNA and initiating immune responses. Excessive STING1 activation can lead to aberrant inflammation and autoinflammatory diseases; therefore, the STING1 degradation pathway is tightly regulated by several negative regulatory mechanisms. In our recent study, we show that the selective autophagy receptor TAX1BP1 functions as a negative regulator of STING1 signaling. TAX1BP1 promotes the degradation of activated STING1 through microautophagy by facilitating the interaction of STING1 with the ESCRT-0 protein HGS, and selective autophagy of the Golgi apparatus in a process known as Golgiphagy. In TAX1BP1-deficient macrophages, STING1 aggregates accumulate at the trans-Golgi network, leading to stronger antiviral and inflammatory responses. These findings support a novel mechanism linking organelle quality control and innate immune regulation, highlighting Golgiphagy as an important feedback mechanism that limits STING1 signaling.

CGAS-STING1通路（CGAS-STING1 pathway）在检测胞质DNA并启动免疫应答中发挥关键作用。过度激活的STING1可引发异常炎症与自身炎症性疾病，因此STING1的降解通路受到多种负调控机制的严格调控。本团队最新研究证实，选择性自噬受体（selective autophagy receptor）TAX1BP1可作为STING1信号通路的负调控因子：TAX1BP1通过促进STING1与ESCRT-0蛋白（ESCRT-0 protein）HGS的相互作用，经由微自噬（microautophagy）途径介导活化型STING1的降解，并参与被称为高尔基自噬（Golgiphagy）的高尔基体选择性自噬过程。在TAX1BP1缺陷型巨噬细胞中，STING1聚集体会在反式高尔基体网络（trans-Golgi network）处累积，从而引发更强的抗病毒与炎症应答。本研究结果揭示了一条连接细胞器质量控制与固有免疫（innate immune）调控的全新机制，并凸显高尔基自噬作为限制STING1信号通路的重要负反馈调控途径。