由于ATF6α和ATF6β的双击而导致的细胞功能的部分限制和未折叠的蛋白质反应通路的补偿调制
Ryoko Akai1, Hisayo Hamashima1, Michiko Saito2
1Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
Cell stress & chaperones
|February 6, 2024
概括
这项研究生成了ATF6双淘汰赛小鼠,以调查内质网膜 (ER) 应激. 这些小鼠显示ATF6α和ATF6β表现出基因剂量依赖的冗余性,并在ER应激反应中发挥不同的作用.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 哺乳动物细胞通过ATF6,IRE1和PERK感知内等质网膜 (ER) 压力.
- ATF6充当转录因子,激活像BiP这样的抗ER压力基因.
- ATF6α和ATF6β是已知的同类物质,但由于双淘汰赛模型中的胚胎致死性,它们在体内联合的功能仍然不清楚.
研究的目的:
- 研究ATF6α和ATF6β的生理作用,通过产生可行的ATF6双击球 (DKO) 小鼠.
- 分析ATF6缺失对胰腺β细胞功能和葡萄糖平衡的影响.
- 描述系统ATF6 DKO小鼠的发育异常,并了解基因剂量依赖冗余性.
主要方法:
- 使用Cre/loxP技术生成ATF6 DKO小鼠,绕过胚胎死亡率.
- 在特定的DKO模型中分析胰腺β细胞功能,胰岛素生产/分泌和葡萄糖耐受性.
- 检查各种ATF6 DKO基因型中的发育表型和胚胎纤维细胞功能.
主要成果:
- 胰腺β细胞特异性ATF6 DKO小鼠表现出降低的葡萄糖耐受性,胰岛素的产生/分泌受损,以及轻微的IRE1/PERK激活.
- 系统ATF6 DKO小鼠表现出基因剂量依赖的胚胎致死性,ATF6α和ATF6β显示功能冗余.
- 在ATF6α和ATF6β之间观察到BiP诱导能力的明显差异.
结论:
- 在哺乳动物的发育和ER应激反应中,ATF6α和ATF6β起着至关重要的,部分冗余的作用.
- 这项研究提供了关于ATF6类似物在维持细胞和有机体平衡中的复杂相互作用的见解.
- 可行的ATF6 DKO模型是剖析这些ER应力调节器的具体贡献的重要工具.
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