title: Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress.
abstract: Oxidative protein folding in the endoplasmic reticulum (ER) has emerged as a potentially significant source of cellular reactive oxygen species (ROS). Recent studies suggest that levels of ROS generated as a byproduct of oxidative folding rival those produced by mitochondrial respiration. Mechanisms that protect cells against oxidant accumulation within the ER have begun to be elucidated yet many questions still remain regarding how cells prevent oxidant-induced damage from ER folding events. Here we report a new role for a central well-characterized player in ER homeostasis as a direct sensor of ER redox imbalance. Specifically we show that a conserved cysteine in the lumenal chaperone BiP is susceptible to oxidation by peroxide, and we demonstrate that oxidation of this conserved cysteine disrupts BiP's ATPase cycle. We propose that alteration of BiP activity upon oxidation helps cells cope with disruption to oxidative folding within the ER during oxidative stress.
authors: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors: Jie
authors: J
authors: Wang
authors: Department of Molecular Medicine, Cornell University, Ithaca, United States.
authors: Kristeen A
authors: KA
authors: Pareja
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors: Chris A
authors: CA
authors: Kaiser
authors: Department of Molecular Medicine, Cornell University, Ithaca, United States css224@cornell.edu.
authors: Carolyn S
authors: CS
authors: Sevier
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D017930:Genes, Reporter; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007763:Lac Operon; D008958:Models, Molecular; D010084:Oxidation-Reduction; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D000251:Adenosine Triphosphatases; D003545:Cysteine
keywords: BiP; Ero1; ROS; endoplasmic reticulum; oxidative folding