The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, U.K.
Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
Biochem J. 2021 Dec 10;478(23):4119-4136. doi: 10.1042/BCJ20210646.
The ERK5 MAP kinase signalling pathway drives transcription of naïve pluripotency genes in mouse Embryonic Stem Cells (mESCs). However, how ERK5 impacts on other aspects of mESC biology has not been investigated. Here, we employ quantitative proteomic profiling to identify proteins whose expression is regulated by the ERK5 pathway in mESCs. This reveals a function for ERK5 signalling in regulating dynamically expressed early embryonic 2-cell stage (2C) genes including the mESC rejuvenation factor ZSCAN4. ERK5 signalling and ZSCAN4 induction in mESCs increases telomere length, a key rejuvenative process required for prolonged culture. Mechanistically, ERK5 promotes ZSCAN4 and 2C gene expression via transcription of the KLF2 pluripotency transcription factor. Surprisingly, ERK5 also directly phosphorylates KLF2 to drive ubiquitin-dependent degradation, encoding negative feedback regulation of 2C gene expression. In summary, our data identify a regulatory module whereby ERK5 kinase and transcriptional activities bi-directionally control KLF2 levels to pattern 2C gene transcription and a key mESC rejuvenation process.
ERK5 MAP 激酶信号通路驱动小鼠胚胎干细胞（mESCs）中原始多能性基因的转录。然而，ERK5 如何影响 mESC 生物学的其他方面尚未得到研究。在这里，我们采用定量蛋白质组学分析来鉴定 ERK5 通路在 mESCs 中调控表达的蛋白质。这揭示了 ERK5 信号在调控动态表达的早期胚胎 2 细胞阶段（2C）基因中的作用，包括 mESC 再活化因子 ZSCAN4。ERK5 信号和 ZSCAN4 在 mESCs 中的诱导增加了端粒长度，这是延长培养所必需的关键再活化过程。在机制上，ERK5 通过转录多能性转录因子 KLF2 促进 ZSCAN4 和 2C 基因的表达。令人惊讶的是，ERK5 还直接磷酸化 KLF2 以驱动泛素依赖性降解，编码 2C 基因表达的负反馈调节。总之，我们的数据确定了一个调节模块，ERK5 激酶和转录活性双向控制 KLF2 水平，以调节 2C 基因转录和关键的 mESC 再活化过程。
