title: Transition metals activate TFEB in overexpressing cells.
abstract: Transition metal toxicity is an important factor in the pathogenesis of numerous human disorders, including neurodegenerative diseases. Lysosomes have emerged as important factors in transition metal toxicity because they handle transition metals via endocytosis, autophagy, absorption from the cytoplasm and exocytosis. Transcription factor EB (TFEB) regulates lysosomal biogenesis and the expression of lysosomal proteins in response to lysosomal and/or metabolic stresses. Since transition metals cause lysosomal dysfunction, we proposed that TFEB may be activated to drive gene expression in response to transition metal exposure and that such activation may influence transition metal toxicity. We found that transition metals copper (Cu) and iron (Fe) activate recombinant TFEB and stimulate the expression of TFEB-dependent genes in TFEB-overexpressing cells. In cells that show robust lysosomal exocytosis, TFEB was cytoprotective at moderate levels of Cu exposure, decreasing oxidative stress as reported by the expression of heme oxygenase-1 (HMOX1) gene. However, at high levels of Cu exposure, particularly in cells with low levels of lysosomal exocytosis, activation of overexpressed TFEB was toxic, increasing oxidative stress and mitochondrial damage. Based on these data, we conclude that TFEB-driven gene network is a component of the cellular response to transition metals. These data suggest limitations and disadvantages of TFEB overexpression as a therapeutic approach.
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15206, U.S.A.
authors.forename: Karina A
authors.initials: KA
authors.lastname: Peña
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15206, U.S.A. kiselyov@pitt.edu.
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis*; D002712:Chlorides / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D028561:Transition Elements / Q000494:pharmacology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002712:Chlorides; D005290:Ferric Compounds; C064972:TFEB protein, human; D028561:Transition Elements; D003300:Copper; C029892:cupric chloride; C024555:ferric chloride
keywords: copper; lysosomes; transcription factor; transcription factor EB (TFEB); transition metals