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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids* / metabolism
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Mammals / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Microphthalmia-Associated Transcription Factor* / genetics
  • Microphthalmia-Associated Transcription Factor* / metabolism
  • Nutrients
  • Protein Stability

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • Microphthalmia-Associated Transcription Factor
  • Amino Acids
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors