Microprotein PLUM encoded by Lin28b uORF is a cytoplasmic determinant of pluripotency and embryonic development

Zhihong Hao, Yi Wu, Yile Huang, Maolei Zhang, Yang Liu, Yueqiao Li, Wenxin Li, Zifeng Ruan, Jian Zhang, Yingzhe Ding, Linpeng Li, Guangsuo Xing, Zichao Liu, Yanshuang Zhou, Qi Wang, Keshi Chen, Wuming Wang, Gang Lu, Dajiang Qin, Wai-Yee Chan and Xingguo Liu ()
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Zhihong Hao: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Yi Wu: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Yile Huang: Chinese Academy of Sciences, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation
Maolei Zhang: Tianfu Jincheng Laboratory, Frontiers Medical Center
Yang Liu: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Yueqiao Li: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Wenxin Li: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Zifeng Ruan: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Jian Zhang: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Yingzhe Ding: Chinese Academy of Sciences, Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation
Linpeng Li: Chinese Academy of Sciences, State Key Lab of Respiratory Disease, Joint School of Life Sciences, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health
Guangsuo Xing: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Zichao Liu: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Yanshuang Zhou: Chinese Academy of Sciences, State Key Lab of Respiratory Disease, Joint School of Life Sciences, Guangzhou Medical University; Guangzhou Institutes of Biomedicine and Health
Qi Wang: Wannan Medical College, School of Basic Medicine
Keshi Chen: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health
Wuming Wang: The Chinese University of Hong Kong, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine
Gang Lu: The Chinese University of Hong Kong, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine
Dajiang Qin: Guangzhou Medical University, Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital
Wai-Yee Chan: The Chinese University of Hong Kong, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine
Xingguo Liu: Chinese Academy of Sciences, Institute of Development and Regeneration, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The crosstalk between translation and metabolism is fundamental for cellular plasticity. While most studies focus on translation within canonical coding regions, the roles of non-canonical open reading frames (ORFs) in metabolic regulation and early development remain unclear. Here, we show that selective translation of an upstream ORF in the 5′ untranslated region (UTR) of Lin28b produces an 85-amino acid microprotein, PLUM (pluripotency-associated Lin28b uORF-encoded microprotein). Depletion of PLUM leads to deterministic and synchronized (near 100%) induction of naïve pluripotency and causes embryo implantation defects in vivo. Mechanistically, PLUM depletion dissolves L1td1 condensates and enhances L1td1 binding to pluripotency mRNAs such as Tfcp2l1 and Zfp42, stabilizing them and promoting coordinated gene activation. Concurrently, PLUM loss disrupts P-bodies enriched with a subset of nuclear-encoded mitochondrial mRNA, potentially preventing their degradation. Together, these alterations trigger an early burst of mitochondrial oxidative phosphorylation and synchronized naïve gene expression, accelerating acquisition of the naïve state. Our study identifies the novel uORF-encoded microprotein PLUM as a pluripotency determinant integrating RNA regulation and metabolic remodeling.

Date: 2025
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DOI: 10.1038/s41467-025-66297-4

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