mTOR-dependent phosphorylation controls TFEB nuclear export

Gennaro Napolitano, Alessandra Esposito, Heejun Choi, Maria Matarese, Valerio Benedetti, Chiara Di Malta, Jlenia Monfregola, Diego Luis Medina, Jennifer Lippincott-Schwartz and Andrea Ballabio ()
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Gennaro Napolitano: Telethon Institute of Genetics and Medicine (TIGEM)
Alessandra Esposito: Telethon Institute of Genetics and Medicine (TIGEM)
Heejun Choi: Howard Hughes Medical Institute
Maria Matarese: Telethon Institute of Genetics and Medicine (TIGEM)
Valerio Benedetti: Telethon Institute of Genetics and Medicine (TIGEM)
Chiara Di Malta: Telethon Institute of Genetics and Medicine (TIGEM)
Jlenia Monfregola: Telethon Institute of Genetics and Medicine (TIGEM)
Diego Luis Medina: Telethon Institute of Genetics and Medicine (TIGEM)
Jennifer Lippincott-Schwartz: Howard Hughes Medical Institute
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract During starvation the transcriptional activation of catabolic processes is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient refeeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data on TFEB nucleo-cytoplasmic shuttling suggest an unpredicted role of mTOR in nuclear export.

Date: 2018
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DOI: 10.1038/s41467-018-05862-6

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