Dysregulation of proteolytic enzymes has huge impact on epidermal homeostasis, which can result in severe pathological conditions such as fibrosis or Netherton syndrome. The metalloprotease meprin β was found to be upregulated in hyperproliferative skin diseases. AP-1 transcription factor complex has been reported to induce Mep1b expression. Since AP-1 and its subunit fos-related antigen 2 (fra-2) are associated with the onset and progression of psoriasis, we wanted to investigate if this could partially be attributed to increased meprin β activity. Here, we demonstrate that fra-2 transgenic mice show increased meprin β expression and proteolytic activity in the epidermis. To avoid influence by other fra-2 regulated genes, we additionally generated a mouse model that enabled tamoxifen-inducible expression of meprin β under the Krt5-promotor to mimic the pathological condition. Interestingly, induced meprin β expression in the epidermis resulted in hyperkeratosis, hair loss and mottled pigmentation of the skin. Employing N-terminomics revealed syndecan-1 as a substrate of meprin β in skin. Shedding of syndecan-1 at the cell surface caused delayed calcium-induced differentiation and impaired adhesion of keratinocytes, which was blocked by the meprin β inhibitor fetuin-B.

蛋白水解酶的失调对表皮稳态具有巨大影响，可导致严重的病理状况，例如纤维化或 Netherton 综合征。发现金属蛋白酶 meprin β 在过度增殖性皮肤病中上调。据报道，AP-1 转录因子复合物可诱导Mep1b表达。由于 AP-1 及其亚基 fos 相关抗原 2 (fra-2) 与银屑病的发病和进展有关，我们想研究这是否部分归因于 meprin β 活性的增加。在这里，我们证明了 fra-2 转基因小鼠在表皮中表现出增加的 meprin β 表达和蛋白水解活性。为了避免其他 fra-2 调节基因的影响，我们另外生成了一个小鼠模型，该模型能够在 Krt5 启动子下实现他莫昔芬诱导的 meprin β 表达以模拟病理状况。有趣的是，表皮中诱导的 meprin β 表达导致皮肤角化过度、脱发和斑驳的色素沉着。使用 N-terminomics 揭示了 syndecan-1 作为皮肤中 meprin β 的底物。