浙江大学林世贤、美国芝加哥大学和深圳湾实验室葛韵研究组合作探明，O-乙酰基葡萄糖胺酰化（O-GlcNAc化）决定了YTHDF蛋白的翻译调控和相分离。相关论文于2023年11月9日发表在《自然—细胞生物学》杂志上。

他们报告了蛋白质翻译后修饰控制YTHDF蛋白生物学功能的机制。他们发现YTHDF1和YTHDF3，而不是YTHDF2，携带高水平的营养传感O-GlcNAc化修饰。O-GlcNAc化通过阻断YTHDF1和YTHDF3与mRNA翻译相关蛋白的相互作用，减弱了它们的翻译促进功能。他们进一步证明，O-GlcNAc化对YTHDF1和YTHDF3的修饰可以调节应力颗粒的组装、稳定性和拆卸，从而更好地从应力中恢复。因此，他们的研究结果发现了YTHDF功能的重要调控途径，为mRNA N6 -甲基腺苷(m6A)的转录后调控功能增加了一层复杂性。

据介绍, m6A是哺乳动物中最丰富的内部mRNA核苷酸修饰，调节细胞生理和分化的关键方面。YTHDF蛋白是m6A修饰的主要识别者，并在细胞质中发挥m6A的生理功能。阐明YTHDF蛋白的调控机制是理解m6A生物学的关键。

附：英文原文

Title: O-GlcNAcylation determines the translational regulation and phase separation of YTHDF proteins

Author: Chen, Yulin, Wan, Ruixi, Zou, Zhongyu, Lao, Lihui, Shao, Guojian, Zheng, Yingying, Tang, Ling, Yuan, Ying, Ge, Yun, He, Chuan, Lin, Shixian

Issue&Volume: 2023-11-09

Abstract: N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAcylation attenuates the translation-promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF3 regulate the assembly, stability and disassembly of stress granules to enable better recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A. Chen et al. report that the YTHDF family of m6A-RNA-binding proteins can be differentially regulated by the post-translational modification O-GlcNAcylation, leading to differential regulation of the YTHDF proteins on translation and phase separation.

DOI: 10.1038/s41556-023-01258-x

Source: https://www.nature.com/articles/s41556-023-01258-x