Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling

Hao Gu, Qidong Li, Shan Huang, Weiguang Lu, Fangyuan Cheng, Ping Gao, Chen Wang, Lin Miao, Yide Mei, Mian Wu

Research output: Contribution to journalArticle

Abstract

Embryonic stem cells (ESCs) possess pluripotency, which is the capacity of cells to differentiate into all lineages of the mature organism. Increasing evidence suggests that the pluripotent state of ESCs is regulated by a combination of extrinsic and intrinsic factors. The underlying mechanisms, however, are not completely understood. Here, we show that March5, an E3 ubiquitin ligase, is involved in maintaining mouse-ESC (mESC) pluripotency. Knockdown of March5 in mESCs led to differentiation from naive pluripotency. Mechanistically, as a transcriptional target of Klf4, March5 catalyses K63-linked polyubiquitination of Prkar1a, a negative regulatory subunit of PKA, to activate PKA, thereby inhibiting the Raf/MEK/ERK pathway. Moreover, March5 is able to replace a MEK/ERK inhibitor to maintain mESC pluripotency under serum-free culture conditions. In addition, March5 can partially replace the use of Klf4 for somatic cell reprogramming. Collectively, our study uncovers a role for the Klf4-March5-PKA-ERK pathway in maintaining the stemness properties of mESCs.

Original languageEnglish (US)
Article number7112
JournalNature communications
Volume6
DOIs
StatePublished - Jun 2 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Gu, H., Li, Q., Huang, S., Lu, W., Cheng, F., Gao, P., Wang, C., Miao, L., Mei, Y., & Wu, M. (2015). Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling. Nature communications, 6, [7112]. https://doi.org/10.1038/ncomms8112