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USP7保护TFEB免受蛋白质酶介导的降解
Swati Keshri1, Mariella Vicinanza1, Michael Takla1
1Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, UK; UK Dementia Research Institute, Cambridge Biomedical Campus, Cambridge, UK.
Cell reports
|October 16, 2024
概括
乌比奎丁特异性蛋白酶7 (USP7) 通过消除降解信号来稳定主调节器转录因子EB (TFEB). 这一发现对于理解TFEB调节和开发癌症疗法至关重要.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 转录因子EB (TFEB) 是 lysosomal生物发生和自的主调节者.
- TFEB的失调与代谢异常和某些癌症有关.
研究的目的:
- 为了确定TFEB的新型调节者.
- 阐明控制TFEB稳定性和功能的翻译后机制.
主要方法:
- 核互原子分析以确定TFEB结合蛋白.
- 基因耗尽和药理上抑制USP7.7.
- 乌比基因定位测试用于确定USP7在TFEB上的杜比基因酶活性.
- 功能性测试评估TFEB介导的转录活性,自流和溶酶体生物发生.
主要成果:
- 乌比奎丁特异性蛋白酶7 (USP7) 被确定为TFEB的关键核相互作用者和后翻译调节器.
- USP7在K116,K264和K274处二基化TFEB,特别是去除与K48结合的多基化.
- 抑制USP7导致TFEB降解,TFEB转录活性受损,自和溶酶体生物发生变化.
- USP7 保持了TFEB在核和细胞质两部分的稳定性.
结论:
- USP7作为一个关键的二维基基因酶,保护TFEB免受蛋白质体降解.
- USP7在维持TFEB介导的细胞反应中发挥着至关重要的作用,包括对营养缺乏的细胞反应.
- USP7-TFEB轴代表了涉及TFEB失调的疾病的潜在治疗标,例如某些癌症.
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