title: A novel role for human sulfiredoxin in the reversal of glutathionylation.
abstract: Modification of protein cysteine residues by disulfide formation with glutathione (glutathionylation) is a reversible posttranslational modification of critical importance in controlling cell signaling events following oxidative and/or nitrosative stress. Here, we show that human sulfiredoxin, a small redox protein conserved in eukaryotes, can act as a novel regulator of the redox-activated thiol switch in cells by catalyzing deglutathionylation of a number of distinct proteins in response to oxidative and/or nitrosative stress. Actin and protein tyrosine phosphatase 1B were identified in vitro as targets of sulfiredoxin 1 (Srx1)-dependent deglutathionylation and confirmed in vivo by two-dimensional gel electrophoresis analysis. In addition, we show that Srx1-dependent deglutathionylation is functionally relevant through restoration of phosphatase activity. Human sulfiredoxin contains one cysteine residue (Cys(99)) that is conserved in all family members. Mutation of the cysteine residue inhibits deglutathionylation but did not affect its capacity to bind intracellular proteins. Furthermore, sulfiredoxin is not an acceptor molecule for the GS(-) moiety during the reaction process. Using two-dimensional gel electrophoresis, we identified multiple protein targets in vivo that are deglutathionylated by sulfiredoxin following oxidative and/or nitrosative stress. This novel deglutathionylation function of sulfiredoxin suggests it has a central role in redox control with potential implications in cell signaling.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Medical University of South Carolina, Jonathan Lucas Street, Charleston, SC 29425, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.forename: Taylor E
authors.initials: TE
authors.lastname: Morris
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Fraser
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D001391:Azo Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D062366:para-Aminobenzoates
chemical_list: D000199:Actins; D001391:Azo Compounds; C485370:O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate; D062366:para-Aminobenzoates; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C504024:SRXN1 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione; D010129:4-Aminobenzoic Acid