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

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.

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Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-66297-4
Citations
1
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.81
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article

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

Wai‐Yee Chan, Zifeng Ruan, Maolei Zhang, Wuming Wang et al.
1 citations
Nature Communications
RNA Research and Splicing
0.81
article

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

Wai‐Yee Chan, Zifeng Ruan, Maolei Zhang, Wuming Wang, Xingguo Liu, Zichao Liu, Yi Wu, Gang Lü, Dajiang Qin, Keshi Chen, Yanshuang Zhou, Zhihong Hao, Yueqiao Li, Guangsuo Xing, Linpeng Li, Yile Huang, Qi Wang, Yang Liu, Wenxin Li, Jian Zhang, Yingzhe Ding
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
Wannan Medical College (CN), Department of Health (CN), Jinan University (CN), Chinese University of Hong Kong (HK), Chinese Academy of Sciences (CN), Guangzhou Institutes of Biomedicine and Health (CN), State Key Laboratory of Respiratory Disease (CN), University of Chinese Academy of Sciences (CN), University of Hong Kong (HK), Guangzhou Medical University (CN)
Openalex Percentile: Top 21%
RNA Research and Splicing
0.81
DOIOpen Access PDFOpenAlex
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