Next-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells

Yi Hao, Xinqi Fan, Yujie Shi, Che Zhang, Sun De-en, Ke Qin, Wei Qin, Wen Zhou and Xing Chen ()
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Yi Hao: Peking University
Xinqi Fan: Peking University
Yujie Shi: Peking University
Che Zhang: Peking University
Sun De-en: Peking University
Ke Qin: Peking University
Wei Qin: Peking University
Wen Zhou: Peking University
Xing Chen: Peking University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Unnatural monosaccharides such as azidosugars that can be metabolically incorporated into cellular glycans are currently used as a major tool for glycan imaging and glycoproteomic profiling. As a common practice to enhance membrane permeability and cellular uptake, the unnatural sugars are per-O-acetylated, which, however, can induce a long-overlooked side reaction, non-enzymatic S-glycosylation. Herein, we develop 1,3-di-esterified N-azidoacetylgalactosamine (GalNAz) as next-generation chemical reporters for metabolic glycan labeling. Both 1,3-di-O-acetylated GalNAz (1,3-Ac2GalNAz) and 1,3-di-O-propionylated GalNAz (1,3-Pr2GalNAz) exhibit high efficiency for labeling protein O-GlcNAcylation with no artificial S-glycosylation. Applying 1,3-Pr2GalNAz in mouse embryonic stem cells (mESCs), we identify ESRRB, a critical transcription factor for pluripotency, as an O-GlcNAcylated protein. We show that ESRRB O-GlcNAcylation is important for mESC self-renewal and pluripotency. Mechanistically, ESRRB is O-GlcNAcylated by O-GlcNAc transferase at serine 25, which stabilizes ESRRB, promotes its transcription activity and facilitates its interactions with two master pluripotency regulators, OCT4 and NANOG.

Date: 2019
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DOI: 10.1038/s41467-019-11942-y

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