LIF促进Sec15b介导的STAT3外体分泌,以维持小鼠胚胎发育中的干细胞多能性
Li Xu1, Jinjun Ji1, Lingbo Wang2,3
1College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|October 30, 2024
概括
在小鼠胚胎干细胞 (mESC) 中的白血病抑制因子 (LIF) 信号传递涉及通过多胞体内体 (MVEs) 分泌STAT3. 这一过程平衡了ERK和GSK3β通路,这对自我更新和造血系统稳定性至关重要.
科学领域:
- 细胞生物学 细胞生物学
- 发展生物学 发展生物学
- 干细胞生物学 干细胞生物学
背景情况:
- 白血病抑制因子 (LIF) 对于通过激活STAT3.3来维持小鼠胚胎干细胞 (mESC) 自更新至关重要.
- 同样由LIF激活的ERK信号通路,在自我更新过程中对抗多能基因诱导.
- 均衡这些途径的调节机制对于mESC多能性至关重要.
研究的目的:
- 研究STAT3转位和分泌在mESC自我更新中的作用.
- 阐明在这个过程中涉及的STAT3的分子相互作用和翻译后修改.
- 确定破坏STAT3-Secl5b相互作用对胚胎发育和造血系统的体内后果.
主要方法:
- 利用mESC培养系统研究STAT3本地化和修改.
- 使用生物化学测试来分析STAT3乙化和酸化.
- 通过共免疫沉,研究了STAT3与Secl5b (EXOC6B) 的相互作用.
- 生成并分析转基因小鼠 (STAT3替代突变和Secl5b淘汰),以评估体内功能.
主要成果:
- 由LIF激活的STAT3经过乙化 (K177/180) 和化 (Y293),促进与Secl5b的相互作用和转移到多胞体内分体 (MVEs) 进行分泌.
- STAT3 MVEs的转移下调ERK1/2酸化,并上调GSK3β酸化,保持mESC的自我更新.
- 在STAT3乙化/化部位的突变或Secl5b的淘汰会损害STAT3分泌,导致部分胚胎致死性和严重的造血异常.
结论:
- 通过Secl5b介导的STAT3 MVEs转位是一种新的机制,用于调节ERK和GSK3β信号平衡以实现mESC自我更新.
- 这一途径对于在胚胎发育过程中维持造血系统稳定性至关重要.
- 破坏STAT3分泌会对发育产生深远的后果,突出显示其重要性超出了核功能.
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