title: Glutathione is required to regulate the formation of native disulfide bonds within proteins entering the secretory pathway.
abstract: The formation of native disulfide bonds is an essential event in the folding and maturation of proteins entering the secretory pathway. For native disulfides to form efficiently an oxidative pathway is required for disulfide bond formation and a reductive pathway is required to ensure isomerization of non-native disulfide bonds. The oxidative pathway involves the oxidation of substrate proteins by PDI, which in turn is oxidized by endoplasmic reticulum oxidase (Ero1). Here we demonstrate that overexpression of Ero1 results in the acceleration of disulfide bond formation and correct protein folding. In contrast, lowering the levels of glutathione within the cell resulted in acceleration of disulfide bond formation but did not lead to correct protein folding. These results demonstrate that lowering the level of glutathione in the cell compromises the reductive pathway and prevents disulfide bond isomerization from occurring efficiently, highlighting the crucial role played by glutathione in native disulfide bond formation within the mammalian endoplasmic reticulum.
authors.affiliation: School of Biological Sciences, The Michael Smith Building, University of Manchester, Manchester, M13 9PT United Kingdom.
authors.forename: Seema
authors.initials: S
authors.lastname: Chakravarthi
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Bulleid
mesh_terms: D000818:Animals; D012634:Bodily Secretions / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism*; D007536:Isomerism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D017510:Protein Folding; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D004220:Disulfides; D008562:Membrane Glycoproteins; D005978:Glutathione