近日，浙江大学万伟等研究人员合作发现，cGAS-STING通路通过激活转录因子TFEB来刺激溶酶体生成和病原清除。该项研究成果于2024年12月16日在线发表在《免疫》杂志上。

研究人员表示，自噬的诱导是环磷酸鸟苷-AMP合成酶（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，自噬货物被运输到溶酶体进行降解。然而，cGAS-STING通路是否也调节溶酶体功能仍然未知。

研究人员发现cGAS-STING通路通过不依赖于下游蛋白激酶TANK结合激酶1（TBK1）的方式，上调溶酶体活性，进而刺激溶酶体的生成。STING激活通过诱导转录因子EB（TFEB）的核转位以及其同源物转录因子E3（TFE3）和小眼畸形相关转录因子（MITF）的核转位，从而增强了溶酶体的生成。STING诱导的GABA型A受体相关蛋白（GABARAP）脂化作用是TFEB激活的关键。

膜结合的GABARAP通过捕获GTP酶激活蛋白folliculin（FLCN）及其相互作用蛋白（FNIP）复合物，阻止其对Rag GTP酶Ras相关GTP结合C和D（RagC和RagD）的作用，从而消除了雷帕霉素机制靶标（mTOR）复合物1（mTORC1）依赖的TFEB磷酸化与失活。功能上，STING诱导的溶酶体生成促进了细胞内细胞质DNA和入侵病原体的清除。

因此，该研究发现，溶酶体生成的诱导是cGAS-STING通路的另一个重要功能。

附：英文原文

Title: The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance

Author: Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan

Issue&Volume: 2024-12-16

Abstract: 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.

DOI: 10.1016/j.immuni.2024.11.017

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00532-6