Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling
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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.
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KLF4 can specifically bind to the phosphorylated forms of STAT3 (p-STAT3) and inhibit its expression.
“KLF4 can specifically bind to the phosphorylated forms of STAT3 (p-STAT3) and inhibit its expression.30”
From Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression (2022) · cites this paper as [30]
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References 46 · Cited by 40
Research works printed but not linked: 1
- Shi H. X.. Mitochondrial ubiquitin ligase MARCH5 promotes TLR7 signaling by attenuating TANK action. PLoS Pathog. 7, e1002057 (2011). 21625535 PMC3098239
- Authors
- Gu, H., Li, Q., Huang, S., Lu, W., Cheng, F., Gao, P., Wang, C., Miao, L., Mei, Y., & Wu, M.
- Affiliations
- University of Science and Technology of China (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Miao, Lin
- Mei, Yide
- Wu, Mian
- ORCID
- Venue
- Nature Communications
- Published
- 2015-06-02
- Volume
- 6
- Issue
- 1
- Pages
- 7112-7112
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4458872
- OpenAlex
- W2106277245
- Cited by
- 40
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 7
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Natural Science Foundation of China (31371388, 81101525)
- Chinese Academy of Sciences (XDA01020104, 2011CB966302)
- Natural Science Foundation of Anhui Province
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- MARCH5, E3 ubiquitin ligase, embryonic stem cells, pluripotency, stemness maintenance, ERK signaling, Raf/MEK/ERK pathway, KLF4, PRKAR1A, K63-linked ubiquitination, protein kinase A, somatic cell reprogramming, naive pluripotency, serum-free culture
- MeSH terms
- Mouse Embryonic Stem Cells, Kruppel-Like Factor 4, Animals, Cell Differentiation, Fluorescent Antibody Technique, Humans, Blotting, Western, Cyclic AMP-Dependent Protein Kinases, Reverse Transcriptase Polymerase Chain Reaction, MAP Kinase Signaling System, Mitochondrial Proteins, Ubiquitin-Protein Ligases, raf Kinases, Mice, Kruppel-Like Transcription Factors, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Ubiquitination, Gene Knockdown Techniques, HEK293 Cells, Real-Time Polymerase Chain Reaction, In Vitro Techniques
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