0519 Involucrin-casein kinase 1e-vitamin D receptor is a functional regulatory axis for human skin evolution and diversity
Recommended Citation
Yao Y, Hicks A, Schmidt A, Mathyer M, de Guzman Strong C. 0519 Involucrin-casein kinase 1e-vitamin D receptor is a functional regulatory axis for human skin evolution and diversity. J Invest Dermatol 2025; 145(8):S89.
Document Type
Conference Proceeding
Publication Date
8-1-2025
Publication Title
J Invest Dermatol
Abstract
We recently discovered that the human skin barrier evolved out-of-Africa. A haplotype for increased involucrin (IVL) expression underwent a near selective sweep in N. European populations in contrast to those in Africa. Ivl positively impacts Vitamin D receptor (Vdr) activity as Ivl-/- mice exhibited a dampened response to Vdr-mediated skin inflammation. Yet the nature and mechanism by which IVL regulates VDR activity that is environmentally sensitive is not known. We examined the significance of this IVL/VDR regulatory axis in primary mouse and diverse human keratinocytes (KCs) using biochemical studies. Ivl-/- mouse KCs exhibited a significant decrease in nuclear Vdr upon vitamin D agonist (MC903) treatment, resulting in decreased Vdr target Tslp, Vdr, and Fos gene expressions. The finding identifies the Ivl-Vdr axis to be cell-intrinsic and transcriptionally active. We further these MC903 studies in dark pigmented, primary human KCs of non-N. European ancestry that also exhibited low IVL and decreased nuclear VDR compared to that of N. European origin of higher IVL, demonstrating functional conservation for this IVL-VDR axis that is calibrated by IVL dosage for human skin barrier evolution and diversity. Multi-omics using ATAC-seq, RNA-seq and LC-MS proteomics in Ivl-/- and wt mouse skin identified Casein kinase 1e (Ck1e) as a putative molecule mediating involucrin’s regulation of Vdr. We identify an Ivl/CK1e/Vdr interactome as evidenced by immunoprecipitation of Ivl and Ck1e with Vdr in differentiated KCs. Ck1e inhibition in MC903-treated HaCAT and mouse KCs resulted in a significant decrease in nuclear VDR and TSLP expression, with lower migrating VDR band in human KCs revealing CK1e phosphorylation of VDR that was confirmed by λ phosphatase treatment. Taken together, we identify a functional IVL/CK1e/VDR regulatory axis whose dosage for IVL underlies human skin barrier evolution and diversity out-of-Africa.
Volume
145
Issue
8
First Page
S89
