Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whey acidic protein Four-Disulfide Core (WFDC) proteins, such as PI3 and SLPI, inhibit proteases in the epidermis and other tissues. Here, we tested the hypothesis that further WFDC protein family members might contribute to epidermal homeostasis. We found that in addition to PI3 and SLPI, WFDC5 and WFDC12 were expressed in human epidermis. In contrast to WFDC5, expression of WFDC12 was induced during late differentiation of keratinocytes (KCs) and restricted to the outermost layer of live cells. Single-cell RNA sequencing demonstrated that WFDC12-positive KCs were characterized by upregulation of late cornified envelope protein expression and downregulated expression of keratins and claudins. Immunogold-electron microscopy revealed co-localization of WFDC12 with corneodesmosomes in the lower stratum corneum. WFDC12 was elevated in affected skin of patients with psoriasis, atopic dermatitis and Darier disease. By contrast, WFDC12 expression was strongly upregulated not only in affected, but even more so in clinically normal appearing skin of Netherton syndrome patients. Finally, functional analysis showed distinct inhibitory activity of WFDC12 on neutrophil elastase and epidermal kallikrein-related peptidase. Altogether, our study identified WFDC12 as a marker of the last stage of epidermal KC differentiation and suggests that WFDC12 contributes to the control of protease activity in the stratum corneum.
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PMID:The whey acidic protein WFDC12 is specifically expressed in terminally differentiated keratinocytes and regulates epidermal serine-protease activity. 3315 95