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A conserved cysteine‐based redox mechanism sustains TFEB/HLH‐30 activity under persistent stress
Author(s) -
Martina José A,
GuerreroGómez David,
GómezOrte Eva,
Antonio Bárcena José,
Cabello Juan,
MirandaVizuete Antonio,
Puertollano Rosa
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105793
Subject(s) - library science , ibis , medicine , biology , ecology , computer science
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.