Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
Department of Child Dental and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
Commun Biol. 2023 Sep 23;6(1):976. doi: 10.1038/s42003-023-05360-6.
Oral lichen planus (OLP), a chronic inflammatory disorder, is characterized by the massive cell apoptosis in the keratinocytes of oral mucosa. However, the mechanism responsible for triggering oral keratinocyte apoptosis is not fully explained. Here, we identify that Gasdermin C (GSDMC) downregulation contributes to apoptosis in human oral keratinocytes. Mechanistically, we describe that activated nuclear factor kappa B (NF-κB) pathway induces overexpression of methyltransferase-like 14 (METTL14), which increases N-adenosine methylation (mA) levels in the epithelial layer of OLP. mA modification is capable of regulating primary miR-6858 processing and alternative splicing, leading to miR-6858 increases. miR-6858 can bind and promote GSDMC mRNA degradation. Forced expression of GSDMC is able to rescue cell apoptosis in human oral keratinocyte models resembling OLP. Collectively, our data unveil that mA modification regulates miR-6858 production to decrease GSDMC expression and to trigger keratinocyte apoptosis in the context of OLP.
口腔扁平苔藓（OLP）是一种慢性炎症性疾病，其特征是口腔黏膜角质形成细胞发生大量细胞凋亡。然而，引发口腔角质形成细胞凋亡的机制尚不完全清楚。在这里，我们发现 Gasdermin C（GSDMC）下调导致人口腔角质形成细胞凋亡。在机制上，我们描述了激活的核因子 kappa B（NF-κB）通路诱导甲基转移酶样 14（METTL14）的过度表达，这增加了 OLP 上皮层中的 N-腺苷甲基化（mA）水平。mA 修饰能够调节初级 miR-6858 的加工和选择性剪接，导致 miR-6858 的增加。miR-6858 可以结合并促进 GSDMC mRNA 的降解。强制表达 GSDMC 能够挽救类似于 OLP 的人口腔角质形成细胞模型中的细胞凋亡。总之，我们的数据揭示了 mA 修饰通过调节 miR-6858 的产生来降低 GSDMC 的表达，并在 OLP 背景下引发角质形成细胞凋亡。
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