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.
Highlights
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
In the presence of nutrients TFEB is phosphorylated by mechanistic target of rapamycin on S142 and S211 serine residues, which play a crucial role in determining TFEB subcellular localization
We found that TFEB continuously shuttles between the cytosol and the nucleus and that the nutrient-dependent modulation of nuclear export rates plays a major role in controlling TFEB subcellular localization
Summary
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. 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). In the presence of nutrients TFEB is phosphorylated by mechanistic target of rapamycin (mTOR) on S142 and S211 serine residues, which play a crucial role in determining TFEB subcellular localization. Upon starvation or lysosomal stress, inhibition of mTOR and concomitant activation of the phosphatase calcineurin by TRPML1-mediated lysosomal calcium release induces TFEB dephosphorylation This results in a nuclear localization of TFEB22. We found that TFEB continuously shuttles between the cytosol and the nucleus and that the nutrient-dependent modulation of nuclear export rates plays a major role in controlling TFEB subcellular localization. Our data highlight a new mechanism controlling TFEB subcellular localization and activity via the modulation of nuclear export
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