棕化许可 RIPK1 激酶活性和TNF通路中的细胞毒性
Na Zhang1, Jianping Liu2, Rui Guo2
1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 101408, China.
Molecular cell
|October 29, 2024
概括
S-palmitoylation激活了与受体相互作用的氨酸/氨酸蛋白激酶1 (RIPK1) 激酶活性,在细胞死亡检查点失败时驱动炎症性疾病. 这种由DHHC5介导的修改为这些疾病提供了潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
背景情况:
- 受体相互作用的氨酸/氨酸蛋白激酶1 (RIPK1) 激酶活性通过亡和亡驱动炎症性疾病.
- 细胞死亡检查点通常抑制RIPK1激酶活性,以防止有害影响.
研究的目的:
- 阐明在细胞死亡检查点被禁用时许可RIPK1激酶活性的机制.
- 在炎症背景下识别RIPK1激酶活性的新型修饰和调节剂.
主要方法:
- 通过生物化学和细胞分析,研究了S-palmitoylation在调节RIPK1激酶活性中的作用.
- 利用TNF刺激和细胞死亡检查点阻塞模型.
- 检查了DHHC5和K63相关的泛基化在RIPK1棕化中的参与.
- 在代谢功能障碍相关的脂肪肝炎的小鼠模型中分析了RIPK1棕化.
主要成果:
- 识别了S-palmitoylation作为RIPK1激酶活性的许可修改.
- 证明TNF诱导RIPK1的棕化,由DHHC5介导,并且依赖于K63连接的无化.
- 表明棕化增强了RIPK1激酶活性,通过促进激酶域同类相互作用,导致检查点阻塞时的细胞死亡.
- 在患有代谢功能障碍相关的脂肪肝炎的小鼠的脂肪肝中发现了DHHC5放大,与增加的RIPK1细胞毒性相关.
结论:
- 取决于ubiquitination的棕化释放RIPK1激酶活性,驱动下游细胞死亡信号.
- 在炎症性疾病中,RIPK1棕化是促进细胞死亡的关键机制,特别是在检查点失效的情况下.
- RIPK1棕化是治疗炎症疾病的潜在治疗点.
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