Xu Yinfeng, Wang Qian, Wang Jun, Qian Chuying, Wang Yusha, Lu Sheng, Song Lijiang, He Zhengfu, Liu Wei, Wan Wei
Laboratory of Basic Biology, Hunan First Normal University, Changsha 410205, Hunan, China.
Department of Thoracic Surgery of Sir Run Run Shaw Hospital, and Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
Immunity. 2025 Feb 11;58(2):309-325.e6. doi: 10.1016/j.immuni.2024.11.017. Epub 2024 Dec 16.
Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.
自噬的诱导是环磷酸鸟苷-腺苷酸（cGAMP）合成酶（cGAS）-干扰素基因刺激因子（STING）通路的一种古老功能，通过该通路自噬货物被递送至溶酶体进行降解。然而，溶酶体功能是否也受cGAS-STING通路调控仍不清楚。在此，我们发现cGAS-STING通路通过独立于下游蛋白激酶TANK结合激酶1（TBK1）刺激溶酶体生物发生来上调溶酶体活性。STING激活通过诱导转录因子EB（TFEB）及其旁系同源物转录因子E3（TFE3）和小眼相关转录因子（MITF）的核转位来增强溶酶体生物发生。STING诱导的自噬相关蛋白A型γ-氨基丁酸受体相关蛋白（GABARAP）在STING囊泡上的脂化负责TFEB的激活。膜结合的GABARAP隔离了GTP酶激活蛋白卵泡抑素（FLCN）和FLCN相互作用蛋白（FNIP）复合物，以阻断其对Rag GTP酶Ras相关GTP结合蛋白C和D（RagC和RagD）的作用，消除雷帕霉素机制靶点（mTOR）复合物1（mTORC1）依赖性的TFEB磷酸化和失活。在功能上，STING诱导的细胞内溶酶体生物发生促进了细胞质DNA和入侵病原体的清除。因此，我们的研究结果揭示了溶酶体生物发生的诱导是cGAS-STING通路的另一重要功能。
