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An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis

Title
An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis
Authors
Bin, Bum-HoBhin, JinhyukKim, Nan-HyungLee, Su-HyonJung, Haeng-SunSeo, JuyeonKim, Dae-KyumHwang, DaeheeFukada, ToshiyukiLee, Ai-YoungLee, Tae RyongCho, Eun-Gyung
DGIST Authors
Hwang, Daehee
Issue Date
2017-04
Citation
Journal of Investigative Dermatology, 137(4), 874-883
Type
Article
Article Type
Article
Keywords
Ehlers Danlos SyndromeEpithelial StratificationMetallothioneinMolecular SwitchP63ProliferationProteinSkinStem CellZinc Transporter
ISSN
0022-202X
Abstract
Acrodermatitis enteropathica is an autosomal recessive disorder characterized by scaly eczematous dermatosis accompanied by alopecia and diarrhea. Various mutations in the SLC39A4 gene (ZIP4), which encodes a zinc transporter, are responsible for this disorder. However, the molecular mechanism underlying the involvement of ZIP4 in the pathogenesis of this condition has yet to be established. In this study, we report the role of ZIP4 in human epidermis. ZIP4 is predominantly expressed in human keratinocytes, and its expression is dramatically reduced on epidermal differentiation. ZIP4 knockdown in human keratinocytes down-regulates zinc (Zn) levels and the transcriptional activity of a key epidermal Zn-binding protein, ΔNp63, and dysregulates epidermal differentiation in a reconstituted human skin model, resulting in the appearance of proliferating keratinocytes even in the uppermost layers of the skin. We verified that, among the amino acid residues in its Zn-binding motif, Cys205 is critical for the processing and nuclear distribution of ΔNp63 and, therefore, Zn-dependent transcriptional activity. Our results suggest that ZIP4 is essential for maintaining human epidermal homeostasis through the regulation of Zn-dependent ΔNp63 activity and can provide insight into the molecular mechanisms responsible for the cutaneous symptoms observed in Acrodermatitis enteropathica patients. © 2016 The Authors
URI
http://hdl.handle.net/20.500.11750/4203
DOI
10.1016/j.jid.2016.11.028
Publisher
Elsevier B.V.
Related Researcher
  • Author Hwang, Dae Hee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
Files:
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Collection:
New BiologyETC1. Journal Articles
ETC1. Journal Articles


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