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Vol. 13, Issue 12, 4371-4387, December 2002

Alternative Splicing Regulates the Subcellular Localization of Divalent Metal Transporter 1 Isoforms

Mitsuaki Tabuchi,^* Naotaka Tanaka, Junko Nishida-Kitayama,^* Hiroshi Ohno, and Fumio Kishi^§

 ^*Center for Gene Research, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan;  Division of Molecular Membrane Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan; and  ^§Department of Microbiology and Immunology, Kagoshima University Dental School, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

Divalent metal transporter 1 (DMT1) is responsible for dietary-iron absorption from apical plasma membrane in the duodenum and iron acquisition from the transferrin cycle endosomes in peripheral tissues. Two isoforms of the DMT1 transcript generated by alternative splicing of the 3' exons have been identified in mouse, rat, and human. These isoforms can be distinguished by the different C-terminal amino acid sequences and by the presence (DMT1A) or absence (DMT1B) of an iron response element located in the 3' untranslated region of the mRNA. However, it has been still unknown whether the structural differences between the two DMT1 isoforms is functionally important. Here, we report that each DMT1 isoform exhibits a differential cell type-specific expression patterns and distinct subcellular localizations. DMT1A is predominantly expressed by epithelial cell lines, whereas DMT1B is expressed by the blood cell lines. In HEp-2 cells, GFP-tagged DMT1A is localized in late endosomes and lysosomes, whereas GFP-tagged DMT1B is localized in early endosomes. Using site-directed mutagenesis, a Y⁵⁵⁵XLXX sequence in the cytoplasmic tail of DMT1B has been identified as an important signal sequence for the early endosomal-targeting of DMT1B. In polarized MDCK cells, GFP-tagged DMT1A and DMT1B are localized in the apical plasma membrane and their respective specific endosomes. Disruption of the N-glycosylation sites in each of the DMT1 isoforms affects their polarized distribution into the apical plasma membrane but not their correct endosomal localization. Our data indicate that the cell type-specific expression patterns and the distinct subcellular localizations of two DMT1 isoforms may be involved in the different iron acquisition steps from the subcellular membranes in various cell types.

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Corresponding author. E-mail address: mtabuchi{at}po.cc.yamaguchi-u.ac.jp.

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Molecular Biology of the Cell
Vol. 13, 4371-4387, December 2002
Copyright © 2002 by The American Society for Cell Biology

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