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J. Biol. Chem., Vol. 281, Issue 14, 9650-9658, April 7, 2006
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EDEM3, a Soluble EDEM Homolog, Enhances Glycoprotein Endoplasmic Reticulum-associated Degradation and Mannose Trimming*
11¶¶||2
From the
Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan, CREST, JST, Saitama 332-0012, Japan, the ¶Department of Cell Sciences, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, the ||Department of Chemistry, Osaka University Graduate School of Science, Toyonaka 560-0043, Japan and **McGill Cancer Centre, Montréal, Québec H3G 1Y6, Canada
Quality control in the endoplasmic reticulum ensures that only properly folded proteins are retained in the cell through mechanisms that recognize and discard misfolded or unassembled proteins in a process called endoplasmic reticulum-associated degradation (ERAD). We previously cloned EDEM (ER degradation-enhancing 
-mannosidase-like protein) and showed that it accelerates ERAD of misfolded glycoproteins. We now cloned mouse EDEM3, a soluble homolog of EDEM. EDEM3 consists of 931 amino acids and has all the signature motifs of Class I -mannosidases (glycosyl hydrolase family 47) in its N-terminal domain and a protease-associated motif in its C-terminal region. EDEM3 accelerates glycoprotein ERAD in transfected HEK293 cells, as shown by increased degradation of misfolded 1-antitrypsin variant (null (Hong Kong)) and of TCR. Overexpression of EDEM3 also greatly stimulates mannose trimming not only from misfolded 1-AT null (Hong Kong) but also from total glycoproteins, in contrast to EDEM, which has no apparent 1,2-mannosidase activity. Furthermore, overexpression of the E147Q EDEM3 mutant, which has the mutation in one of the conserved acidic residues essential for enzyme activity of 1,2-mannosidases, abolishes the stimulation of mannose trimming and greatly decreases the stimulation of ERAD by EDEM3. These results show that EDEM3 has 1,2-mannosidase activity in vivo, suggesting that the mechanism whereby EDEM3 accelerates glycoprotein ERAD is different from that of EDEM.
Received for publication, November 14, 2005 , and in revised form, January 4, 2006.
* This work was supported by Grant-in-aid 17370039 (to I. W.), Grant-in-aid 16207013 (to K. N.), Grants-in-aid 17046009 and 17570161 (to N. H.) from the Ministry of Education, Culture, Sports, and Technology of Japan and by Grant MOP-74714 from the Canadian Institutes of Health Research (to A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These two authors contributed equally to this work.
2 To whom correspondence should be addressed: Dept. of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan. Tel.: 81-75-751-3849; Fax: 81-75-751-4646; E-mail: nobuko{at}frontier.kyoto-u.ac.jp.
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