The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates 1 – 3 . However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy 4 , 5 , is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB—unlike other substrates of mTORC1, such as S6K and 4E-BP1— is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin ( FLCN ) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma 6 , 7 . We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt–Hogg–Dubé syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer. Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.

中文翻译：

---

底物特异性 mTORC1 通路是 Birt-Hogg-Dubé 综合征的基础

雷帕霉素复合物 1 (mTORC1) 的机制靶点是一个关键的代谢中心，它通过在多种底物上发挥其激酶活性来控制细胞对环境信号的反应 1 – 3。然而，人们对 mTORC1 是否通过差异磷酸化特定底物对多种刺激作出反应却知之甚少。在这里，我们显示转录因子 EB (TFEB)，溶酶体生物发生和自噬的主要调节因子 4, 5，通过由 Rag GTPase 介导的底物特异性机制被 mTORC1 磷酸化。由于这种机制，TFEB 的磷酸化——与 mTORC1 的其他底物不同，如 S6K 和 4E-BP1——严格依赖于氨基酸介导的 RagC 和 RagD GTPase 的激活，但对生长诱导的 RHEB 活性不敏感因素。这种机制在 Birt-Hogg-Dubé 综合征中起着至关重要的作用，一种由 RagC 和 RagD 激活因子卵泡蛋白 (FLCN) 突变引起的疾病，其特征是良性皮肤肿瘤、肺和肾囊肿以及肾细胞癌 6、7。我们发现 TFEB 的组成型激活是 Birt-Hogg-Dubé 综合征小鼠模型中肾脏异常和 mTORC1 过度活跃的主要驱动因素。因此，这些小鼠肾脏中 TFEB 的消耗完全挽救了疾病表型和相关的致死率，并使 mTORC1 活性正常化。我们的研究结果确定了一种机制，该机制使 mTORC1 底物的差异磷酸化成为可能，其失调导致肾囊肿和癌症。mTORC1 底物特异性机制的失调导致 TFEB 的组成型激活，并促进 Birt-Hogg-Dubé 综合征小鼠模型中的肾囊肿和肿瘤发生。