title: Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress.
abstract: Redox fluctuations within cells can be detrimental to cell function. To gain insight into how cells normally buffer against redox changes to maintain cell function, we have focused on elucidating the signaling pathways that serve to sense and respond to oxidative redox stress within the endoplasmic reticulum (ER) using yeast as a model system. Previously, we have shown that a cysteine in the molecular chaperone BiP, a Hsp70 molecular chaperone within the ER, is susceptible to oxidation by peroxide during ER-derived oxidative stress, forming a sulfenic acid (-SOH) moiety. Here, we demonstrate that this same conserved BiP cysteine is susceptible also to glutathione modification (-SSG). Glutathionylated BiP is detected both as a consequence of enhanced levels of cellular peroxide and also as a by-product of increased levels of oxidized glutathione (GSSG). Similar to sulfenylation, we observe glutathionylation decouples BiP ATPase and peptide binding activities, turning BiP from an ATP-dependent foldase into an ATP-independent holdase. We show glutathionylation enhances cell proliferation during oxidative stress, which we suggest relates to modified BiP's increased ability to limit polypeptide aggregation. We propose the susceptibility of BiP to modification with glutathione may serve also to prevent irreversible oxidation of BiP by peroxide.
authors: From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853.
authors: Jie
authors: J
authors: Wang
authors: From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853 css224@cornell.edu.
authors: Carolyn S
authors: CS
authors: Sevier
mesh_terms: D002470:Cell Survival; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010545:Peroxides / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D010545:Peroxides; D005978:Glutathione; D003545:Cysteine
keywords: 70-kilodalton heat shock protein (Hsp70); BiP; GRP78; Kar2; endoplasmic reticulum (ER); glutathionylation; molecular chaperone; oxidative stress; redox signaling