核糖体相关蛋白质的O-GlcNAcylation与蛋白质毒性压力期间的翻译重编程并发
Quira Zeidan1, Jie L Tian2, Junfeng Ma1
1Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
The Journal of biological chemistry
|October 12, 2024
概括
蛋白质O-GlcNAc的修饰会影响蛋白质的稳态和翻译. 这项研究揭示了它在压力期间恢复蛋白质合成中的作用,以及它可能与瘤对蛋白酶抑制剂的耐药性有关.
科学领域:
- 生物化学和分子生物学
- 细胞应激反应的应激反应
- 癌症生物学 癌症生物学
背景情况:
- 蛋白质O-GlcNAc修饰调节重要的细胞过程,但其在蛋白质平衡中的作用,包括合成,折叠和降解,尚不清楚.
- O-GlcNAc循环酶与翻译机制相关,修改核糖体蛋白质.
- 蛋白质翻译与26S蛋白质酶活性有关,这对于清除压力期间错误折叠的蛋白质至关重要.
研究的目的:
- 研究O-GlcNAc修饰在蛋白质平衡中的作用,特别是与蛋白质合成和蛋白质酶活性的联系.
- 探索O-GlcNAc循环酶,翻译机制和应激反应之间的相互作用.
- 为了确定特定的O-GlcNAc修饰蛋白质,参与维持压力下的蛋白质合成.
主要方法:
- 药理学蛋白质酶抑制观察O-GlcNAc酶局部化和蛋白质修饰.
- 对O-GlcNAc修饰,无处不在和转化重编程 (eIF2α依赖) 的分析.
- O-GlcNAc-丰富,其次是LC-MS/MS以识别修饰的蛋白质;免疫光用于蛋白质的同位化.
主要成果:
- 蛋白质酶抑制增加了O-GlcNAc转移酶 (OGT) 和O-GlcNAcase (OGA) 在富含核糖体的部分,与转化蛋白的O-GlcNAc修饰相关.
- O-GlcNAc的新陈代谢会影响受压力的细胞中的蛋白质泛化.
- 在55种蛋白质上确定了84个独特的O-GlcNAc位点,包括核糖体蛋白和Hsp70家族成员.
- OGT和Hsp70与翻译机器同位,帮助蛋白质合成在压力期间恢复.
结论:
- 在核糖体相关蛋白质上循环的O-GlcNAc与HSP70合作,在蛋白质毒性期间恢复蛋白质合成.
- 这种O-GlcNAc介导的机制表明它在瘤对蛋白酶体抑制剂的抗性中起着作用.
- 突出了O-GlcNAc修饰在压力条件下维持细胞功能的重要性.
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