April 2017 - Vol 137 No 4

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ZIP4, one of a large family of zinc binding proteins, is encoded by the SLC39A4 gene that, when mutated, causes the recessive disorder acrodermatitis enteropathica, characterized by severe dermatitis, alopecia, and diarrhea. In this issue, Bin et al examine its role in human epidermis. They find that ZIP4 is expressed by proliferating keratinocytes in vitro and in vivo and that ZIP4 knockdown (KD) by short interfering (si) RNA reduces intracellular zinc levels. In a reconstituted human skin model ZIP4 KD (siZIP4) versus an irrelevant KD control (siControl) epidermis shows abnormal morphology with greatly reduced filaggrin and keratin 14 (KRT14) and increased involucrin (protein staining shown in brown in the left-hand image). ZIP4 KD constructs also show nuclei (Nu) in the uppermost epidermal layers that stain for proliferating cell nuclear antigen (PCNA), an abnormality not seen in controls (right-hand image). The investigators further show that ZIP4 acts by regulating p63, a known zinc-binding transcription factor that orchestrates epidermal differentiation. For details and other findings, see the article on page 874.