EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
Nobuko HosokawaKazuhiro Nagata

Abstract

Misfolded glycoproteins are degraded by a mechanism known as ERAD (ER-associated degradation) after retrotranslocation out of the endoplasmic reticulum (ER). This mechanism plays an important role in ER quality control. We previously reported that an ER membrane protein, EDEM, accelerates ERAD of a misfolded alpha1-antitrypsin variant, null (Hong Kong) (NHK), suggesting that EDEM may function as an acceptor of terminally misfolded glycoproteins. In this study, we constructed several genetically manipulated cell lines to test this hypothesis. EDEM expression did not alter the secretion rate of properly folded molecules and the forced retention of wild-type alpha1-antitrypsin in the ER did not cause its association with EDEM, suggesting that EDEM may function as a molecular chaperone. To examine this possibility, we analyzed the effect of EDEM over-expression on the structure of NHK, and found that the accumulation of covalent NHK dimers was selectively prevented by the over-expression of EDEM. Co-expression of NHK with two other ER membrane proteins, calnexin and H(+)/K(+)-ATPase (beta subunit), did not inhibit NHK dimer formation or accelerate NHK ERAD. These results indicate that EDEM may maintain the retrotranslocation compet...Continue Reading

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Citations

Dec 14, 2007·Histochemistry and Cell Biology·Jürgen RothChristian Zuber
Jan 9, 2010·The Journal of Biological Chemistry·Yoshimi SugiuraKazuhiro Nagata
Sep 22, 2012·The Journal of Biological Chemistry·Marion BouchecareilhWilliam E Balch
Aug 5, 2011·Molecular Biology of the Cell·Yang ChenKazuo Yamamoto
Jan 13, 2010·Glycobiology·Nobuko HosokawaAnnette Herscovics
Nov 20, 2009·Journal of Biochemistry·Jun HosekiKazuhiro Nagata
Aug 31, 2011·Cold Spring Harbor Perspectives in Biology·Kazutaka Araki, Kazuhiro Nagata
Nov 26, 2009·Journal of Cell Science·Maria KosmaoglouMichael E Cheetham
Jul 5, 2013·PloS One·Patrícia Isabel MarquesSusana Seixas
Sep 16, 2011·Molecular Biology of the Cell·Efrat RonGerardo Z Lederkremer
Jul 9, 2008·Proceedings of the National Academy of Sciences of the United States of America·Cornelia M WilsonStephen High
May 19, 2007·Nature Chemical Biology·Maurizio Molinari
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