Ufl1 deficiency causes skin pigmentation by u-pregulation of Endothelin-1

Ufmylation (UFM1 modification) is a newly identified ubiquitin-like modification system involved in numerous cellular processes. However, the regulatory mechanisms and biological functions of this modification remain mostly unknown. We have recently reported that Ufmylation family genes have frequent somatic copy number alterations in human cancer including melanoma, suggesting involvement of Ufmylation in skin function and disease. UFL1 is the only known Ufmylation E3-like ligase. In this study, we generated the skin-specific Ufl1 knockout mice and show that ablation of Ufl1 caused epidermal thickening, pigmentation and shortened life span. RNA-Seq analysis indicated that Ufl1 deletion resulted in upregulation of the genes involved in melanin biosynthesis. Mechanistically, we found that Endothelin-1 (ET-1) is a novel substrate of Ufmylation and this modification regulates ET-1 stability, and thereby deletion of Ufl1 upregulates the expression and secretion of ET-1, which in turn results in up-regulation of genes in melanin biosynthesis and skin pigmentation. Our findings establish the role of Ufl1 in skin pigmentation through Ufmylation modification of ET-1 and provide opportunities for therapeutic intervention of skin diseases. Comparative gene expression profiling analysis of RNA-seq data for Wild Type(WT) mice and skin-specific Ufl1 knockout mice ears at 3-months of age.

Ufmylation (UFM1修饰)是新近发现的类泛素修饰系统，参与诸多细胞生物学过程。然而，该修饰的调控机制与生物学功能大多尚不明确。我们近期报道称，Ufmylation家族基因在包括黑色素瘤在内的人类癌症中存在频繁的体细胞拷贝数变异，提示该修饰参与皮肤功能调控与疾病发生。UFL1是目前已知的唯一一类Ufmylation E3样连接酶。本研究构建了皮肤特异性Ufl1敲除小鼠模型，实验结果显示，Ufl1基因敲除可导致表皮增厚、色素沉着，并缩短小鼠寿命。RNA测序（RNA-Seq）分析表明，Ufl1缺失会上调黑色素生物合成相关基因的表达。机制研究显示，内皮素-1（Endothelin-1, ET-1）是Ufmylation的新型底物，该修饰可调控ET-1的蛋白稳定性；因此Ufl1缺失会上调ET-1的表达与分泌，进而促进黑色素合成相关基因的表达上调及皮肤色素沉着。本研究明确了Ufl1通过Ufmylation修饰ET-1参与皮肤色素沉着的作用机制，为皮肤疾病的治疗干预提供了潜在方向。本研究针对3月龄野生型（Wild Type, WT）小鼠与皮肤特异性Ufl1敲除小鼠的耳部组织，开展了RNA测序数据的比较基因表达谱分析。