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Zn2+‐stimulated degradation of hZIP4 zinc transporter is mediated by ubiquitination
Author(s) -
Mao Xiaoqing,
Kim Byung Eun,
Petris Michael J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1352-b
Zinc is an essential trace element in all organisms. Zinc transporters play important roles in maintaining zinc homeostasis. The importance of zinc transporters is highlighted by a genetic disorder acrodermatitis enteropathica (AE), caused by the reduced uptake of dietary zinc. The gene responsible for AE is SLC39A4 , which encodes the human zinc transporter hZIP4. In this study, we first characterized HA‐tagged human hZIP4 protein as a functional zinc transporter. It is degraded under high zinc conditions and this degradation is time‐ and metal ligand‐dependent. Endocytosis is required for its degradation. hZIP4 degradation under high zinc is blocked by proteosome inhibitor, MG132. Furthermore, we showed that the degradation is mediated via ubiquitination pathway. In in vivo Co‐IP experiment, under high zinc condition, but not under zinc deficient condition, FLAG‐ubiquitin can be pulled down using anti‐HA column, which binds HA‐tagged hZIP4 protein. Moreover, hZIP4 protein level is stabilized by ubiquitin‐K48R mutant, further demonstrating the essential role of poly‐ubiquitin chain formation in hZIP4 degradation. This work was supported by National Institutes of Health Grant DK59893, to M.J.P.