A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome

Gennaro Napolitano, Chiara Di Malta, Alessandra Esposito, Mariana E. G. de Araujo, 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 and Andrea Ballabio ()
Additional contact information
Gennaro Napolitano: Telethon Institute of Genetics and Medicine (TIGEM)
Chiara Di Malta: Telethon Institute of Genetics and Medicine (TIGEM)
Alessandra Esposito: Telethon Institute of Genetics and Medicine (TIGEM)
Mariana E. G. de Araujo: Biocenter, Medical University of Innsbruck
Salvatore Pece: IEO, European Institute of Oncology IRCCS
Giovanni Bertalot: IEO, European Institute of Oncology IRCCS
Maria Matarese: Telethon Institute of Genetics and Medicine (TIGEM)
Valerio Benedetti: Telethon Institute of Genetics and Medicine (TIGEM)
Angela Zampelli: Telethon Institute of Genetics and Medicine (TIGEM)
Taras Stasyk: Biocenter, Medical University of Innsbruck
Diletta Siciliano: Telethon Institute of Genetics and Medicine (TIGEM)
Alessandro Venuta: Telethon Institute of Genetics and Medicine (TIGEM)
Marcella Cesana: Telethon Institute of Genetics and Medicine (TIGEM)
Claudia Vilardo: Telethon Institute of Genetics and Medicine (TIGEM)
Edoardo Nusco: Telethon Institute of Genetics and Medicine (TIGEM)
Jlenia Monfregola: Telethon Institute of Genetics and Medicine (TIGEM)
Alessia Calcagnì: Baylor College of Medicine
Pier Paolo Di Fiore: IEO, European Institute of Oncology IRCCS
Lukas A. Huber: Biocenter, Medical University of Innsbruck
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)

Nature, 2020, vol. 585, issue 7826, 597-602

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2444-0

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