mTOR-dependent phosphorylation controls TFEB nuclear export

Napolitano, G.; Esposito, A.; Choi, H.; Benedetti, V.; Matarese, M.; Di Malta, C.; Monfregola, J.; Medina, D. L.; Lippincott-Schwartz, J.; Ballabio, A.

doi:10.1101/339416

bioRxiv · 10.1101/339416

mTOR-dependent phosphorylation controls TFEB nuclear export

Napolitano, G.·Esposito, A.·Choi, H.·Benedetti, V.·Matarese, M.·Di Malta, C.·Monfregola, J.·Medina, D. L.·Lippincott-Schwartz, J.·Ballabio, A.

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Abstract

The transcriptional activation of catabolic processes during starvation 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 re-feeding 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 reveal that modulation of TFEB nuclear export via phosphorylation plays a major role in the modulation of TFEB localization and activity.

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Napolitano, G., Esposito, A., Choi, H., Benedetti, V., Matarese, M., Di Malta, C., Monfregola, J., Medina, D. L., Lippincott-Schwartz, J., Ballabio, A.. 2018-06-05. mTOR-dependent phosphorylation controls TFEB nuclear export. https://doi.org/10.1101/339416

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