2. Academic Validation
  3. A central role for regulated protein stability in the control of TFE3 and MITF by nutrients

A central role for regulated protein stability in the control of TFE3 and MITF by nutrients

  • Mol Cell. 2023 Jan 5;83(1):57-73.e9. doi: 10.1016/j.molcel.2022.12.013.
Christopher Nardone 1,  Brad A Palanski 2,  Daniel C Scott 3,  Richard T Timms 4,  Karl W Barber 1,  Xin Gu 5,  Aoyue Mao 6,  Yumei Leng 1,  Emma V Watson 1,  Brenda A Schulman 7,  Philip A Cole 2,  Stephen J Elledge 8
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Division of Genetics, Department of Medicine, Brigham and Women's Hospital; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge, Cambridgeshire CB2 0AW, UK.
  • 5 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA.
  • 7 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
  • 8 Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: selledge@genetics.med.harvard.edu.
PMID: 36608670 DOI: 10.1016/j.molcel.2022.12.013
Abstract

The TFE3 and MITF master transcription factors maintain metabolic homeostasis by regulating lysosomal, melanocytic, and Autophagy genes. Previous studies posited that their cytosolic retention by 14-3-3, mediated by the Rag GTPases-mTORC1, was key for suppressing transcriptional activity in the presence of nutrients. Here, we demonstrate using mammalian cells that regulated protein stability plays a fundamental role in their control. Amino acids promote the recruitment of TFE3 and MITF to the lysosomal surface via the Rag GTPases, activating an evolutionarily conserved phospho-degron and leading to ubiquitination by CUL1β-TrCP and degradation. Elucidation of the minimal functional degron revealed a conserved alpha-helix required for interaction with RagA, illuminating the molecular basis for a severe neurodevelopmental syndrome caused by missense mutations in TFE3 within the RagA-TFE3 interface. Additionally, the phospho-degron is recurrently lost in TFE3 genomic translocations that cause kidney Cancer. Therefore, two divergent pathologies converge on the loss of protein stability regulation by nutrients.

Keywords

MITF; Rag GTPases; TFE3; kidney cancer; lysosomes; mTORC1; neurodevelopment; nutrient-sensing; phospho-degron; ubiquitin; β-TrCP.

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