毛囊素
TFEB
Birt-Hogg-Dubé综合征
mTORC1型
雷氏菌
细胞生物学
生物
P70-S6激酶1
雷帕霉素的作用靶点
磷酸化
蛋白质稳态
癌症研究
PI3K/AKT/mTOR通路
TSC2
医学
转录因子
信号转导
遗传学
基因
解剖
气胸
作者
Gennaro Napolitano,Chiara Di Malta,Alessandra Esposito,Mariana E. G. de Araújo,Salvatore Pece,Giovanni Bertalot,Maria Matarese,Valerio Benedetti,Angela Zampelli,Taras Stasyk,Diletta Siciliano,Alessandro Venuta,Marcella Cesana,Claudia Vilardo,Edoardo Nusco,Jlenia Monfregola,Alessia Calcagnì,Pier Paolo Di Fiore,Lukas A. Huber,Andrea Ballabio
出处
期刊:Nature
[Springer Nature]
日期:2020-07-01
卷期号:585 (7826): 597-602
被引量:161
标识
DOI:10.1038/s41586-020-2444-0
摘要
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 substrates1-3. 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 autophagy4,5, 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 carcinoma6,7. 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.
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