title: ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER.
abstract: Membrane and secretory proteins cotranslationally enter and are folded in the endoplasmic reticulum (ER). Misfolded or unassembled proteins are discarded by a process known as ER-associated degradation (ERAD), which involves their retrotranslocation into the cytosol. ERAD substrates frequently contain disulfide bonds that must be cleaved before their retrotranslocation. Here, we found that an ER-resident protein ERdj5 had a reductase activity, cleaved the disulfide bonds of misfolded proteins, and accelerated ERAD through its physical and functional associations with EDEM (ER degradation-enhancing alpha-mannosidase-like protein) and an ER-resident chaperone BiP. Thus, ERdj5 is a member of a supramolecular ERAD complex that recognizes and unfolds misfolded proteins for their efficient retrotranslocation.
authors.affiliation: Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ushioda
authors.forename: Jun
authors.initials: J
authors.lastname: Hoseki
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Araki
authors.forename: Gregor
authors.initials: G
authors.lastname: Jansen
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005978:Glutathione / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007144:Immunoglobulin J-Chains / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism
chemical_list: C471179:DNAJC10 protein, human; C530517:ERdj5 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007144:Immunoglobulin J-Chains; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011506:Proteins; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; D011490:Protein Disulfide Reductase (Glutathione); D019704:Protein Disulfide-Isomerases; D005978:Glutathione