Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-β1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-β1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-β1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.

中文翻译：

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SYVN1 通过促进 SIRT2 泛素化和降解在控制气道重塑和哮喘保护中的作用

哮喘是一种以气道重塑为特征的异质性疾病。SYVN1 (Synoviolin 1) 充当 E3 连接酶，通过泛素化和降解介导内质网 (ER) 应激的抑制。然而，SYVN1 在哮喘发病机制中的作用尚不清楚。在本研究中，使用卵清蛋白（OVA）诱导的小鼠模型来评估 SYVN1 对哮喘的作用。OVA 诱导后，在小鼠肺部观察到 SYVN1 表达增加。SYVN1 的过度表达减轻了 OVA 诱导的气道炎症、杯状细胞增生和胶原蛋白沉积。体内 SYVN1 也能抑制内质网应激相关蛋白的增加和上皮间质转化 (EMT) 标记物的改变。接下来，使用TGF-β1诱导的支气管上皮细胞（BEAS-2B）在体外诱导EMT过程。结果显示，TGF-β1刺激下调SYVN1的表达，SYVN1过表达阻止TGF-β1诱导的细胞内质网应激反应和EMT过程。此外，我们还发现 SYVN1 与 SIRT2 结合并促进其泛素化和降解。SIRT2 过表达消除了 SYVN1 对 ER 应激和体外 EMT 的保护作用。这些数据表明，SYVN1 通过 SIRT2 的泛素化和降解来抑制 ER 应激，从而阻断 EMT 过程，从而防止哮喘气道重塑。