title: An unexpected role for the yeast nucleotide exchange factor Sil1 as a reductant acting on the molecular chaperone BiP.
abstract: Unfavorable redox conditions in the endoplasmic reticulum (ER) can decrease the capacity for protein secretion, altering vital cell functions. While systems to manage reductive stress are well-established, how cells cope with an overly oxidizing ER remains largely undefined. In previous work (Wang et al., 2014), we demonstrated that the chaperone BiP is a sensor of overly oxidizing ER conditions. We showed that modification of a conserved BiP cysteine during stress beneficially alters BiP chaperone activity to cope with suboptimal folding conditions. How this cysteine is reduced to reestablish 'normal' BiP activity post-oxidative stress has remained unknown. Here we demonstrate that BiP's nucleotide exchange factor - Sil1 - can reverse BiP cysteine oxidation. This previously unexpected reductant capacity for yeast Sil1 has potential implications for the human ataxia Marinesco-Sjögren syndrome, where it is interesting to speculate that a disruption in ER redox-signaling (due to genetic defects inSIL1) may influence disease pathology.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Siegenthaler
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors.forename: Kristeen A
authors.initials: KA
authors.lastname: Pareja
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors.forename: Carolyn S
authors.identifier: 0000-0003-3245-6988
authors.initials: CS
authors.lastname: Sevier
mesh_terms: D003545:Cysteine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D026901:Membrane Transport Proteins; C513385:SIL1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D003545:Cysteine
keywords: BiP; Hsp70; Kar2; S. cerevisiae; Sil1; biochemistry; cell biology; endoplasmic reticulum; glutathionylation; oxidative stress; redox signaling