title: An Acrodermatitis Enteropathica-Associated Zn Transporter, ZIP4, Regulates Human Epidermal Homeostasis.
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.
authors.affiliation: Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin, Republic of Korea.
authors.forename: Bum-Ho
authors.initials: BH
authors.lastname: Bin
authors.affiliation: Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Bhin
authors.affiliation: Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Nan-Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Bio Solution Corporation, Seoul, Republic of Korea.
authors.forename: Su-Hyon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Bio Solution Corporation, Seoul, Republic of Korea.
authors.forename: Haeng-Sun
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin, Republic of Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Seo
authors.affiliation: Donnelly Centre, Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Dae-Kyum
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukada
authors.affiliation: Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Ai-Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin, Republic of Korea. Electronic address: trlee@amorepacific.com.
authors.forename: Tae Ryong
authors.initials: TR
authors.lastname: Lee
authors.affiliation: Basic Research & Innovation Division, R&D Unit, AmorePacific Corporation, Yongin, Republic of Korea. Electronic address: egcho@amorepacific.com.
authors.forename: Eun-Gyung
authors.initials: EG
authors.lastname: Cho
mesh_terms: D000169:Acrodermatitis / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012494:Sampling Studies; D055815:Young Adult; D015032:Zinc / Q000172:deficiency* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D034741:RNA, Small Interfering; C486791:SLC39A4 protein, human; C017800:zinc-binding protein; D015032:Zinc