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Peer-reviewedCC BY 4.0Frontiers in Cell and Developmental Biology

Conserved phosphorylation events in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells

  • Haojie Duan1
  • Qian Wang2
  • Yuping Suo2
  • Jin-An Zhou3
  • Xiaojuan Liu1
  • Yin Fang1
  1. 1Departments of Laboratory Medicine, Obstetrics & Gynecology and Pediatrics, Cancer Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
  2. 2Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China
  3. 3Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract

Embryonic stem cells are self-renewing, pluripotent cells, normally maintained by several pluripotency transcription factors. To respond to diverse differentiation and stress signaling pathways, the undifferentiated cell state must be destabilized before embryonic stem cells can properly interpret external signals to decide the cell fate. It remains incompletely understood how diverse signals promote the exit of the self-renewal state. Here, we show that both acute DNA damage and diverse differentiation signaling pathways converge at the proteasomal destruction of Estrogen-related receptor β (ESRRB), a key pluripotency transcription factor. Environmental agents such as UV light and genotoxic chemicals activate P-TEFb protein kinase to directly phosphorylate ESRRB to promote its proteasomal degradation. On the other hand, diverse differentiation signaling pathways also promote ESRRB degradation. Interestingly, the responsible kinase is GSK3β, instead of P-TEFb, in these biological contexts. Substituting five Ser residues in ESRRB with Ala confers resistance to GSK3β-dependent ESRRB degradation and compromises cell differentiation. These results demonstrate that conserved post-translational modifications in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells.

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Cite

BibTeXRIS
BibTeX
@article{duan2026conserved,
  title = {{Conserved phosphorylation events in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells}},
  author = {Haojie Duan and Qian Wang and Yuping Suo and Jin-An Zhou and Xiaojuan Liu and Yin Fang},
  journal = {Frontiers in Cell and Developmental Biology},
  year = {2026},
  month = oct,
  doi = {10.3389/fcell.2026.1919736},
  url = {https://doi.org/10.3389/fcell.2026.1919736},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Conserved phosphorylation events in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells
AU  - Haojie Duan
AU  - Qian Wang
AU  - Yuping Suo
AU  - Jin-An Zhou
AU  - Xiaojuan Liu
AU  - Yin Fang
PY  - 2026
DA  - 2026/10/12
JO  - Frontiers in Cell and Developmental Biology
DO  - 10.3389/fcell.2026.1919736
UR  - https://doi.org/10.3389/fcell.2026.1919736
AB  - Embryonic stem cells are self-renewing, pluripotent cells, normally maintained by several pluripotency transcription factors. To respond to diverse differentiation and stress signaling pathways, the undifferentiated cell state must be destabilized before embryonic stem cells can properly interpret external signals to decide the cell fate. It remains incompletely understood how diverse signals promote the exit of the self-renewal state. Here, we show that both acute DNA damage and diverse differentiation signaling pathways converge at the proteasomal destruction of Estrogen-related receptor β (ESRRB), a key pluripotency transcription factor. Environmental agents such as UV light and genotoxic chemicals activate P-TEFb protein kinase to directly phosphorylate ESRRB to promote its proteasomal degradation. On the other hand, diverse differentiation signaling pathways also promote ESRRB degradation. Interestingly, the responsible kinase is GSK3β, instead of P-TEFb, in these biological contexts. Substituting five Ser residues in ESRRB with Ala confers resistance to GSK3β-dependent ESRRB degradation and compromises cell differentiation. These results demonstrate that conserved post-translational modifications in ESRRB integrate diverse signaling pathways to govern the fate of embryonic stem cells.
SN  - 2296-634X
ER  -