Multi-omics analysis reveals dermokine as a regulator of keratinocyte differentiation and adhesion.

Abstract

Impaired adhesion and differentiation of keratinocytes is a hallmark of several skin diseases, but only some of the factors that regulate these processes have been identified. Here, we studied the role of isoform-rich dermokine - a wound- and tumor-regulated protein - in keratinocytes using a combination of multi-omics and functional approaches. CRISPR/Cas9-induced knockout of dermokine isoforms in human keratinocytes inhibited differentiation of these cells in three-dimensional organotypic skin cultures, which was confirmed by quantitative proteomics. In two-dimensional monocultures, dermokine deficiency affected the proteome and phosphoproteome as revealed by mass spectrometry. We found reduced abundance of differentiation-specific proteins and increased phosphorylation of cell adhesion protein p120 (catenin-δ1). The adhesive strength of dermokine knockout keratinocytes was impaired, which was rescued by p120 knock-down or ROCK inhibition. Finally, we verified the correlation between decreased dermokine expression and increased p120 phosphorylation in human non-healing wounds. These results identify dermokine as regulator of keratinocyte adhesion and differentiation, involving at least in part its effect on p120 phosphorylation and ROCK. Our data point to a function of dermokine in the pathogenesis of chronic wounds.