Aberrant expression of the UPF1 RNA surveillance gene disturbs keratinocyte homeostasis by stabilizing AREG
Aberrant expression of the UPF1 RNA surveillance gene disturbs keratinocyte homeostasis by stabilizing AREG
复制标题
UPF1 RNA 监视基因的异常表达通过稳定 AREG 来扰乱角质形成细胞稳态
DOI：
10.3892/ijmm.2020.4487
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发表时间：
2020-04-01
影响因子：
5.4
通讯作者：
Liu，Chen
中科院分区：
文献类型：
--
作者：
Cheng，Yaojia;Lu，Qiuping;Liu，Chen
上移码抑制子1同系物（UPF1） RNA监视基因是无义介导的RNA衰变（NMD）途径的核心元件，它以细胞特异性的方式影响广泛的生物过程。本研究报道了NMD通路在银屑病病变中的作用及其对角质形成细胞生物学过程的调节作用。对两名银屑病患者的皮肤鳞片进行Sanger测序，发现UPF1基因中存在两个mRNA突变（c.2935_2936insA和c.2030-2081del）。体细胞突变体产生截断的UPF1蛋白，扰乱细胞内的NMD通路，导致NMD底物上调。作为角化细胞中最丰富的表皮生长因子受体配体，我们认为双调节蛋白（AREG） mRNA是一种天然的NMD底物，依赖于其3 '非翻译区序列。受干扰的NMD以areg依赖性但不相同的方式调节角化细胞的稳态，这突出了NMD在角化细胞中的独特特征。UPF1-NMD通路通过转录后靶向AREG mRNA，导致角化细胞中增殖与凋亡、异常分化、迁移和炎症反应之间的不平衡，提示NMD通路在角化细胞相关发病和皮肤病的全面发展中发挥了作用。
The up-frameshift suppressor 1 homolog (UPF1) RNA surveillance gene is a core element in the nonsense-mediated RNA decay (NMD) pathway, which impacts a broad spectrum of biological processes in a cell-specific manner. In the present study, the contribution of the NMD pathway to psoriasis lesions and its moderating effects on the biological processes of keratinocytes was reported. Sanger sequencing for skin scales from two patients with psoriasis identified two mRNA mutations (c.2935_2936insA and c.2030-2081del) in the UPF1 gene. The somatic mutants produced truncated UPF1 proteins and perturbed the NMD pathway in cells, leading to the upregulation of NMD substrates. As the most abundant epidermal growth factor receptor ligand in keratinocytes, it was concluded that amphiregulin (AREG) mRNA is a natural NMD substrate, that is dependent on its 3′ untranslated region sequence. Perturbed NMD modulated keratinocyte homeostasis in an AREG-dependent but nonidentical manner, which highlighted the unique characteristics of NMD in keratinocytes. By targeting AREG mRNA post-transcriptionally, the UPF1-NMD pathway contributed to an imbalance between proliferation on the one hand, and apoptosis and abnormal differentiation, migration and inflammatory response on the other, in keratinocytes, which indicated a role of the NMD pathway in the full development of keratinocyte-related morbidity and skin diseases.