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First published online April 1, 2009
doi: 10.1242/10.1242/jcs.037317

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An essential role for ClC-4 in transferrin receptor function revealed in studies of fibroblasts derived from Clcn4-null mice

Raha Mohammad-Panah^1,*, Leigh Wellhauser^1,2,*, Benjamin E. Steinberg³, Yanchun Wang¹, Ling Jun Huan¹, Xiang-Dong Liu⁴ and Christine E. Bear^1,2,

¹ Programme in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, Canada
² Department of Biochemistry, Faculty of Medicine, University of Toronto, Canada
³ Programme in Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, Canada
⁴ Department of Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Canada

Author for correspondence (e-mail: bear{at}sickkids.on.ca)

Accepted 1 December 2008

ClC-4 is closely related to ClC-5, a member of the ClC family of transporters and channels. Unlike ClC-5, for which a role in the regulation of endosomal function was well established, the cellular function of ClC-4 was uncertain. In the present study, we tested for a specific role for ClC-4 in recycling endosomes by comparing transferrin (Tfn) receptor function in primary cell lines generated from ClC-4-null mice and their wild-type siblings. We found that endosomal pH is relatively alkaline and receptor-mediated uptake of Tfn is reduced in ClC-4-null fibroblasts. Surprisingly, this reduction in Tfn uptake occurs, despite a minor increase in the total surface expression of the Tfn receptor in ClC-4-null fibroblasts. As impaired Tfn uptake by ClC-4-null fibroblasts could be rescued to wild-type levels by addition of the iron chelator: desoxiferramine, the primary defect in these cells is related to the failure of iron to dissociate from Tfn, a pH-dependent event in endosomes that precedes the dissociation of Tfn from its receptor at the cell surface. Interestingly, ClC-4 depletion had no effect on epidermal growth factor receptor (EGFR) trafficking to lysosomes for degradation pointing to its specific role in recycling endosomes. These observations provide direct evidence supporting an essential role for ClC-4 in the modulation of Tfn receptor accessibility at the cell surface through its role in endosomal acidification.

Key words: ClC family, Endosomal pH, Primary fibroblast cell line

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