title: Methionine sulfoxide reductase 2 reversibly regulates Mge1, a cochaperone of mitochondrial Hsp70, during oxidative stress.
abstract: Peptide methionine sulfoxide reductases are conserved enzymes that reduce oxidized methionines in protein(s). Although these reductases have been implicated in several human diseases, there is a dearth of information on the identity of their physiological substrates. By using Saccharomyces cerevisiae as a model, we show that of the two methionine sulfoxide reductases (MXR1, MXR2), deletion of mitochondrial MXR2 renders yeast cells more sensitive to oxidative stress than the cytosolic MXR1. Our earlier studies showed that Mge1, an evolutionarily conserved nucleotide exchange factor of Hsp70, acts as an oxidative sensor to regulate mitochondrial Hsp70. In the present study, we show that Mxr2 regulates Mge1 by selectively reducing MetO at position 155 and restores the activity of Mge1 both in vitro and in vivo. Mge1 M155L mutant rescues the slow-growth phenotype and aggregation of proteins of mxr2Δ strain during oxidative stress. By identifying the first mitochondrial substrate for Mxrs, we add a new paradigm to the regulation of the oxidative stress response pathway.
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Allu
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Adinarayana
authors.initials: A
authors.lastname: Marada
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Yerranna
authors.initials: Y
authors.lastname: Boggula
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Karri
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India.
authors.forename: Thanuja
authors.initials: T
authors.lastname: Krishnamoorthy
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, India nareshuohyd@gmail.com nbvssl@uohyd.ernet.in.
authors.forename: Naresh Babu V
authors.initials: NB
authors.lastname: Sepuri
mesh_terms: D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D050505:Mutant Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C086039:MGE1 protein, S cerevisiae; D033681:Mitochondrial Membrane Transport Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; C090869:SSA3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D008715:Methionine; D010088:Oxidoreductases; D051150:Methionine Sulfoxide Reductases; C487505:MXR2 protein, S cerevisiae