A conserved cysteine-based redox mechanism sustains TFEB/HLH-30 activity under persistent stress

EMBO J. 2021 Feb 1;40(3):e105793. doi: 10.15252/embj.2020105793. Epub 2020 Dec 14.


Mammalian TFEB and TFE3, as well as their ortholog in Caenorhabditis elegans HLH-30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress, and pathogen infection. In this study, we identify a novel mechanism of TFEB/HLH-30 regulation through a cysteine-mediated redox switch. Under stress conditions, TFEB-C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1-mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH-30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility in worms. Therefore, cysteine oxidation represents a new type of TFEB post-translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH-30 target genes.

Keywords: HLH-30; TFE3; TFEB; glutathionylation; lysosomes.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line
  • Cysteine
  • HeLa Cells
  • Humans
  • Mice
  • Mutation*
  • Oxidation-Reduction
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • RAW 264.7 Cells


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Caenorhabditis elegans Proteins
  • HLH-30 protein, C elegans
  • TFEB protein, human
  • Tcfeb protein, mouse
  • Cysteine