ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER

Science. 2008 Jul 25;321(5888):569-72. doi: 10.1126/science.1159293.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • Glutathione / metabolism
  • HSP40 Heat-Shock Proteins / chemistry
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunoglobulin J-Chains / chemistry
  • Immunoglobulin J-Chains / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Oxidation-Reduction
  • Protein Disulfide Reductase (Glutathione) / metabolism
  • Protein Disulfide-Isomerases / metabolism
  • Protein Folding
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Transfection
  • Two-Hybrid System Techniques
  • alpha 1-Antitrypsin / chemistry
  • alpha 1-Antitrypsin / metabolism

Substances

  • DNAJC10 protein, human
  • ERdj5 protein, mouse
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Immunoglobulin J-Chains
  • Membrane Proteins
  • Molecular Chaperones
  • Proteins
  • Recombinant Proteins
  • alpha 1-Antitrypsin
  • Protein Disulfide Reductase (Glutathione)
  • Protein Disulfide-Isomerases
  • Glutathione
  • molecular chaperone GRP78