由MNK驱动的eIF4E酸化调节介质细胞的纤维化转化和慢性肺异位移植功能障碍
Natalie M Walker1, Yuta Ibuki1, A Patrick McLinden2
1Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
The Journal of clinical investigation
|August 15, 2024
概括
用抑制剂向MNK/eIF4E通路可以治疗组织纤维化. 这项研究揭示了一种新的信号通路,该通路对介质细胞激活和纤维性疾病至关重要,包括慢性肺异位移植功能障碍.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 翻译医学是一种翻译医学.
背景情况:
- 组织纤维化是慢性移植失败的主要原因,缺乏有效的治疗方法.
- 介酶细胞激活是纤维化的核心,由信号通路与真核细胞翻译启动因子 (eIF4E) 交汇驱动.
研究的目的:
- 为了研究MAP激酶与氨酸/氨酸激酶 (MNK) 相互作用的eIF4E在氨酸209 (Ser209) 处诱导的酸化在介质细胞纤维化转化中的作用.
- 确定MNK/eIF4E途径对慢性肺异位移植功能障碍 (CLAD) 的贡献.
主要方法:
- 在CLAD患者中介细胞中对Ser209的eIF4E酸化的分析.
- 研究了自毒素和β-catenin信号的调节.
- 在体外利用了MNK1活性的遗传和药理抑制.
- 在小鼠肺移植模型中评估了一种MNK1/2抑制剂 (eFT-508).
主要成果:
- 来自CLAD患者的介质细胞显示eIF4E光-Ser209.9的升高.
- eIF4E素-Ser209具有关键调节的自毒素,导致β-catenin激活和益纤维功能.
- 在CLAD介质细胞中,MNK1信号被上调.
- 抑制MNK1降低了eIF4E-Ser209和益纤维功能.
- 在体内,eFT-508治疗预防了全移植纤维化.
结论:
- 确定了一种新的MNK/eIF4E/自毒素/β-catenin信号通路,该通路驱动介质细胞的纤维化转化.
- 证明了MNK抑制剂治疗纤维化症的治疗潜力,包括慢性肺异位移植功能障碍.
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