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Cell:双特异性RNA适配体能够操纵特定靶蛋白的O-GlcNAc糖基化修饰

已有 650 次阅读 2023-1-31 15:26 |系统分类:论文交流

Dual-specificity RNA aptamers enable manipulation of target-specific O-GlcNAcylation and unveil functions of O-GlcNAc on β-catenin

Author: Yi Zhu, Gerald W. Hart

    美国约翰霍普金斯大学 Yi Zhu和Gerald W. Hart发现,双特异性RNA适配体能够操纵特异性靶蛋白的O-GlcNAc糖基化修饰,并揭示O-GlcNAc修饰调控β-catenin蛋白的功能。相关论文于2023年1月9日在线发表于国际学术期刊CELL《细胞》。

    研究人员开发了一种基于双重RNA适配体的方法,同时针对O-GlcNAc转移酶(OGT)和β-catenin(Wnt信号通路的关键转录因子),从而选择性地增加后者的O-GlcNAcylation而不影响其他OGT底物。通过使用OGT/β-catenin双特异性诱导剂,研究人员发现β-catenin的O-Glc修饰通过抑制其与β-TrCP的相互作用而稳定该蛋白。O-GlcNAc修饰还增加了β-catenin与EZH2的相互作用,将EZH2招募到启动子上,并极大地改变了转录组。此外,通过将核糖开关或诱导性表达系统与适配体相连接,研究人员实现了对蛋白质特异性O-GlcNAcylation的诱导性调控。总之,这些研究结果证明了双特异性适配体在调控单个蛋白质的O-GlcNAc修饰方面的功效和多样性。

    O-连接的N-乙酰葡糖胺(O-GlcNAc)修饰是一种动态的翻译后修饰(PTM),可调节蛋白质定位和功能等。在研究O-GlcNAc修饰的调节作用时,一个主要的障碍是无法一次改变单一蛋白质上的O-GlcNAcylation。

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参考文献:Dual-specificity RNA aptamers enable manipulation of target-specific O-GlcNAcylation and unveil functions of O-GlcNAc on β-catenin

Abstract: O-GlcNAc is a dynamic post-translational modification (PTM) that regulates proteinfunctions. In studying the regulatory roles of O-GlcNAc, a major roadblock is theinability to change O-GlcNAcylation on a single protein at a time. Herein, we developeda dual RNA-aptamer-based approach that simultaneously targeted O-GlcNAc transferase(OGT) and β-catenin, the key transcription factor of the Wnt signaling pathway, toselectively increase O-GlcNAcylation of the latter without affecting other OGT substrates.Using the OGT/β-catenin dual-specificity aptamers, we found that O-GlcNAcylation ofβ-catenin stabilizes the protein by inhibiting its interaction with β-TrCP. O-GlcNAcalso increases β-catenin’s interaction with EZH2, recruits EZH2 to promoters, anddramatically alters the transcriptome. Further, by coupling riboswitches or an inducibleexpression system to aptamers, we enabled inducible regulation of protein-specificO-GlcNAcylation. Together, our findings demonstrate the efficacy and versatility ofdual-specificity aptamers for regulating O-GlcNAcylation on individual proteins.

Highlights

•Dual-specificity RNA aptamers regulate O-GlcNAcylation on individual proteins

•O-GlcNAc stabilizes β-catenin by inhibiting its interaction with β-TrCP

•O-GlcNAc on β-catenin recruits EZH2 to promoters and alters transcription

•Dual-specificity aptamers can be controlled by riboswitches or a Tet-On system

Keywords:β-catenin, O-GlcNAc, aptamer, O-GlcNAc transferase,Wnt signaling

post-translational modification,RNA,EZH2,transcriptome riboswitch


DOI: https://doi.org/10.1016/j.cell.2022.12.016 

Full text: https://www.cell.com/cell/fulltext/S0092-8674(22)01529-X 

https://pubmed.ncbi.nlm.nih.gov/36626902/ 




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