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J. Biol. Chem., Vol. 282, Issue 24, 17908-17920, June 15, 2007

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Subcellular Localization and Physiological Significance of Intracellular Mannan-binding Protein^*

Motohiro Nonaka¹, Bruce Yong Ma¹², Misato Ohtani, Akitsugu Yamamoto^¶, Masayuki Murata^||, Kiichiro Totani^**, Yukishige Ito^**, Keiko Miwa, Wataru Nogami, Nobuko Kawasaki, and Toshisuke Kawasaki³

From the Research Center for Glycobiotechnology, Ritsumeikan University, Shiga 525-8577, the Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, the ^¶Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Shiga 526-0829, the ^||Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, and ^**RIKEN (The Institute of Physical and Chemical Research), Saitama 351-0198, Japan

Mannan-binding protein (MBP) is a C-type mammalian lectin specific for mannose and N-acetylglucosamine. MBP is mainly synthesized in the liver and occurs naturally in two forms, serum MBP (S-MBP) and intracellular MBP (I-MBP). S-MBP activates complement in association with MBP-associated serine proteases via the lectin pathway. Despite our previous study (Mori, K., Kawasaki, T., and Yamashina, I. (1984) Arch. Biochem. Biophys. 232, 223-233), the subcellular localization of I-MBP and its functional implication have not been clarified yet. Here, as an extension of our previous studies, we have demonstrated that the expression of human MBP cDNA reproduces native MBP differentiation of S-MBP and I-MBP in human hepatoma cells. I-MBP shows distinct accumulation in cytoplasmic granules, and is predominantly localized in the endoplasmic reticulum (ER) and involved in COPII vesicle-mediated ER-to-Golgi transport. However, the subcellular localization of either a mutant (C236S/C244S) I-MBP, which lacks carbohydrate-binding activity, or the wild-type I-MBP in tunicamycin-treated cells shows an equally diffuse cytoplasmic distribution, suggesting that the unique accumulation of I-MBP in the ER and COPII vesicles is mediated by an N-glycan-lectin interaction. Furthermore, the binding of I-MBP with glycoprotein intermediates occurs in the ER, which is carbohydrate- and pH-dependent, and is affected by glucose-trimmed high-mannose-type oligosaccharides. These results strongly indicate that I-MBP may function as a cargo transport lectin facilitating ER-to-Golgi traffic in glycoprotein quality control.

Received for publication, February 2, 2007 , and in revised form, March 9, 2007.

^* This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas, A-14082203 (to T. K.) and for Scientific Research, C-18590471 (to B. Y. M.) from the Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology of Japan. 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 Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 81-77-561-3450; Fax: 81-77-561-3451; E-mail: byma{at}fc.ritsumei.ac.jp. ³ To whom correspondence may be addressed. Tel.: 81-77-561-3444; Fax: 81-77-561-3496; E-mail: tkawasak{at}fc.ritsumei.ac.jp.

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