title: PEX5, the shuttling import receptor for peroxisomal matrix proteins, is a redox-sensitive protein.
abstract: Peroxisome maintenance depends on the import of nuclear-encoded proteins from the cytosol. The vast majority of these proteins is destined for the peroxisomal lumen and contains a C-terminal peroxisomal targeting signal, called PTS1. This targeting signal is recognized in the cytosol by the receptor PEX5. After docking at the peroxisomal membrane and release of the cargo into the organelle matrix, PEX5 is recycled to the cytosol through a process requiring monoubiquitination of an N-terminal, cytosolically exposed cysteine residue (Cys11 in the human protein). At present, the reason why a cysteine, and not a lysine residue, is the target of ubiquitination remains unclear. Here, we provide evidence that PTS1 protein import into human fibroblasts is a redox-sensitive process. We also demonstrate that Cys11 in human PEX5 functions as a redox switch that regulates PEX5 activity in response to intracellular oxidative stress. Finally, we show that exposure of human PEX5 to oxidized glutathione results in a ubiquitination-deficient PEX5 molecule, and that substitution of Cys11 by a lysine can counteract this effect. In summary, these findings reveal that the activity of PEX5, and hence PTS1 import, is controlled by the redox state of the cytosol. The potential physiological implications of these findings are discussed.
authors.affiliation: Laboratory of Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine, KU, Leuven, Belgium.
authors.forename: Oksana
authors.initials: O
authors.lastname: Apanasets
authors.forename: Cláudia P
authors.initials: CP
authors.lastname: Grou
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Chantal
authors.initials: C
authors.lastname: Brees
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Marcus
authors.initials: M
authors.lastname: Nordgren
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dodt
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Azevedo
authors.forename: Marc
authors.initials: M
authors.lastname: Fransen
mesh_terms: D002460:Cell Line; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000378:metabolism*; D021382:Protein Sorting Signals; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000614264:PEX5 protein, human; D000074435:Peroxisome-Targeting Signal 1 Receptor; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear; D005978:Glutathione; D003545:Cysteine
keywords: PEX5; PTS1; monoubiquitination; oxidative stress; peroxisomes; protein import; redox switch