UBE3C促进了错误折叠的CFTR的ER相关和外围退化
Yuka Kamada1, Hazuki Tateishi1, Uta Nakayamada1
1Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
Cells
|December 9, 2023
概括
E3酶UBE3C有助于通过ER相关降解 (ERAD) 清除错误折叠的CFTR蛋白. 抑制UBE3C可以增强细胞表面的功能CFTR,特别是使用CFTR调节器.
科学领域:
- 细胞生物学 细胞生物学
- 蛋白质降解 蛋白质降解
- 分子机制的分子机制
背景情况:
- 乌比奎丁E3结合酶UBE3C针对细胞质和ER膜蛋白进行蛋白质酶体降解.
- UBE3C与ER相关的降解 (ERAD) 途径有关,可能在RNF185/MBRL的下游作用.
- 了解UBE3C在ERAD中的作用对于涉及蛋白质错折的疾病至关重要,例如囊性纤维化.
研究的目的:
- 调查UBE3C在错误折叠CFTR和其他膜蛋白的ERAD中的作用.
- 为了确定 UBE3C 是否独立于 RNF5/185 ERAD 途径运作.
- 评估与CFTR调节器结合准UBE3C的治疗潜力.
主要方法:
- 在蜂系统中利用了UBE3C敲除 (KD) 模型.
- 评估了错误折叠的CFTR (包括∆F508-CFTR) 和其他蛋白质 (如insig-1和ABCB1.1) 的ERAD.
- 量化CFTR变异和功能通道的细胞表面表达.
- 检查了错误折叠的CFTR的无处不在状态.
主要成果:
- 在RNF5/185.5独立的情况下,UBE3C促进了错误折叠的CFTR的ERAD.
- UBE3C KD在血膜上增强了功能性∆F508-CFTR,特别是使用CFTR调节器.
- UBE3C KD减少了错误折叠的∆Y490-ABCB1的ERAD,增加了它的细胞表面表达.
- UBE3C KD稳定了成熟的∆F508-CFTR,并增加了细胞表面T70-CFTR.
结论:
- 在错误折叠的CFTR和ABCB1的ERAD中,UBE3C通过RNF5/185独立通路发挥着重要作用.
- 准UBE3C可能是一种治疗策略,用于增强囊性纤维化中CFTR功能.
- UBE3C也可能参与CFTR的外围质量控制.
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