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J. Biol. Chem., Vol. 278, Issue 28, 26287-26294, July 11, 2003

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Enhancement of Endoplasmic Reticulum (ER) Degradation of Misfolded Null Hong Kong ₁-Antitrypsin by Human ER Mannosidase I^*

Nobuko Hosokawa   ¶, Linda O. Tremblay ||, Zhipeng You ||, Annette Herscovics ||, Ikuo Wada  **  and Kazuhiro Nagata  

From the Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan, ^||McGill Cancer Centre, McGill University, Montréal, Québec H3G 1Y6, Canada, and ^**Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan

Misfolded glycoproteins synthesized in the endoplasmic reticulum (ER) are degraded by cytoplasmic proteasomes, a mechanism known as ERAD (ER-associated degradation). In the present study, we demonstrate that ERAD of the misfolded genetic variant-null Hong Kong ₁-antitrypsin is enhanced by overexpression of the ER processing 1,2-mannosidase (ER ManI) in HEK 293 cells, indicating the importance of ER ManI in glycoprotein quality control. We showed previously that EDEM, an enzymatically inactive mannosidase homolog, interacts with misfolded ₁-antitrypsin and accelerates its degradation (Hosokawa, N., Wada, I., Hasegawa, K., Yorihuzi, T., Tremblay, L. O., Herscovics, A., and Nagata, K. (2001) EMBO Rep. 2, 415–422). Herein we demonstrate a combined effect of ER ManI and EDEM on ERAD of misfolded ₁-antitrypsin. We also show that misfolded ₁-antitrypsin NHK contains labeled Glc₁Man₉GlcNAc and Man_5–9GlcNAc released by endo--N-acetylglucosaminidase H in pulse-chase experiments with [2-³H]mannose. Overexpression of ER ManI greatly increases the formation of Man₈GlcNAc, induces the formation of Glc₁Man₈GlcNAc and increases trimming to Man_5–7GlcNAc. We propose a model whereby the misfolded glycoprotein interacts with ER ManI and with EDEM, before being recognized by downstream ERAD components. This detailed characterization of oligosaccharides associated with a misfolded glycoprotein raises the possibility that the carbohydrate recognition determinant triggering ERAD may not be restricted to Man₈GlcNAc₂ isomer B as previous studies have suggested.

Received for publication, April 2, 2003 , and in revised form, May 3, 2003.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N. H., I. W., and K. N.) and by a grant 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.

Present address: Dept. of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.

^¶ To whom correspondence should be addressed. Tel.: 81-75-751-3849; Fax: 81-75-751-4646; E-mail: nobuko{at}frontier.kyoto-u.ac.jp.

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