PT - JOURNAL ARTICLE AU - Gennaro Napolitano AU - Alessandra Esposito AU - Heejun Choi AU - Valerio Benedetti AU - Maria Matarese AU - Chiara Di Malta AU - Jlenia Monfregola AU - Diego Luis Medina AU - Jennifer Lippincott-Schwartz AU - Andrea Ballabio TI - mTOR-dependent phosphorylation controls TFEB nuclear export AID - 10.1101/339416 DP - 2018 Jan 01 TA - bioRxiv PG - 339416 4099 - http://biorxiv.org/content/early/2018/06/05/339416.short 4100 - http://biorxiv.org/content/early/2018/06/05/339416.full AB - 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.