2. Academic Validation
  3. mTOR-dependent phosphorylation controls TFEB nuclear export

mTOR-dependent phosphorylation controls TFEB nuclear export

  • Nat Commun. 2018 Aug 17;9(1):3312. doi: 10.1038/s41467-018-05862-6.
Gennaro Napolitano 1 2,  Alessandra Esposito 1,  Heejun Choi 3,  Maria Matarese 1,  Valerio Benedetti 1,  Chiara Di Malta 1,  Jlenia Monfregola 1,  Diego Luis Medina 1,  Jennifer Lippincott-Schwartz 3 4,  Andrea Ballabio 5 6 7
Affiliations

Affiliations

  • 1 Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
  • 2 Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy.
  • 3 Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, 20147, USA.
  • 4 National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5 Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy. ballabio@tigem.it.
  • 6 Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy. ballabio@tigem.it.
  • 7 Department of Molecular and Human Genetics and Neurological Research Institute, Baylor College of Medicine, Houston, TX, 77030, USA. ballabio@tigem.it.
PMID: 30120233 DOI: 10.1038/s41467-018-05862-6
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.

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