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Science 25 July 2008:
Vol. 321. no. 5888, pp. 569 - 572
DOI: 10.1126/science.1159293
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Reports

ERdj5 Is Required as a Disulfide Reductase for Degradation of Misfolded Proteins in the ER

Ryo Ushioda,1* Jun Hoseki,1,2* Kazutaka Araki,1* Gregor Jansen,3 David Y. Thomas,3 Kazuhiro Nagata1,2{dagger}

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.

1 Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan.
2 Core Research for Evolutional Science and Technology, Japan Science Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
3 Biochemistry Department, Faculty of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: nagata{at}frontier.kyoto-u.ac.jp

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection.
Y. Ishida, A. Yamamoto, A. Kitamura, S. R. Lamande, T. Yoshimori, J. F. Bateman, H. Kubota, and K. Nagata (2009)
Mol. Biol. Cell 20, 2744-2754
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Roles of Protein-disulfide Isomerase-mediated Disulfide Bond Formation of Yeast Mnl1p in Endoplasmic Reticulum-associated Degradation.
M. Sakoh-Nakatogawa, S.-i. Nishikawa, and T. Endo (2009)
J. Biol. Chem. 284, 11815-11825
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ERdj5 Sensitizes Neuroblastoma Cells to Endoplasmic Reticulum Stress-induced Apoptosis.
C. G. Thomas and G. Spyrou (2009)
J. Biol. Chem. 284, 6282-6290
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Substrate Specificity of the Oxidoreductase ERp57 Is Determined Primarily by Its Interaction with Calnexin and Calreticulin.
C. E. Jessop, T. J. Tavender, R. H. Watkins, J. E. Chambers, and N. J. Bulleid (2009)
J. Biol. Chem. 284, 2194-2202
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JAMP Optimizes ERAD to Protect Cells from Unfolded Proteins.
M. Tcherpakov, L. Broday, A. Delaunay, T. Kadoya, A. Khurana, H. Erdjument-Bromage, P. Tempst, X.-B. Qiu, G. N. DeMartino, and Z. Ronai (2008)
Mol. Biol. Cell 19, 5019-5028
   Abstract »    Full Text »    PDF »


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