O-GlcNAcylation reduces proteome solubility and regulates the formation of biomolecular condensates in human cells

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Senhan Xu, Kejun Yin, Xing Xu, Longping Fu, Ronghu Wu
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Abstract

O-GlcNAcylation plays critical roles in the regulation of protein functions and cellular activities, including protein interactions with other macromolecules. While the formation of biomolecular condensates (or biocondensates) regulated by O-GlcNAcylation in a few individual proteins has been reported, systematic investigation of O-GlcNAcylation on the regulation of biocondensate formation remains to be explored. Here we systematically study the roles of O-GlcNAcylation in regulating protein solubility and its impacts on RNA-protein condensates using mass spectrometry-based chemoproteomics. Unexpectedly, we observe a system-wide decrease in the solubility of proteins modified by O-GlcNAcylation, with glycoproteins involved in focal adhesion and actin binding exhibiting the most significant decrease. Furthermore, O-GlcNAcylation sites located in disordered regions and with fewer acidic and aromatic residues nearby are related to a greater drop in protein solubility. Additionally, we discover that a specific group of O-GlcNAcylation events promotes the dissociation of RNA-protein condensates under heat stress, while some enhance the formation of RNA-protein condensates during the recovery phase. Using site mutagenesis, inhibition of O-GlcNAc transferase, and fluorescence microscopy, we validate that O-GlcNAcylation regulates the formation of biocondensates for YTHDF3 and NUFIP2. This work advances our understanding of the functions of protein O-GlcNAcylation and its roles in the formation of biomolecular condensates.

Abstract Image

o - glcn酰化降低了蛋白质组的溶解度并调节了人类细胞中生物分子凝聚物的形成
o - glcn酰化在调节蛋白质功能和细胞活动,包括蛋白质与其他大分子的相互作用中起着关键作用。虽然已经报道了o - glcnac酰化在少数单个蛋白质中调节生物分子凝聚物(或生物凝聚物)的形成,但o - glcnac酰化对生物凝聚物形成的调节的系统研究仍有待探索。本文采用基于质谱的化学蛋白质组学技术系统地研究了o - glcn酰化在调节蛋白质溶解度中的作用及其对rna -蛋白质凝聚体的影响。出乎意料的是,我们观察到被o - glcn酰化修饰的蛋白质的溶解度在全系统范围内下降,其中参与局灶粘附和肌动蛋白结合的糖蛋白的下降最为显著。此外,o - glcnac酰化位点位于无序区域,并且附近的酸性和芳香残基较少,这与蛋白质溶解度的较大下降有关。此外,我们发现一组特定的o - glcn酰化事件促进了热应激下rna -蛋白凝聚体的解离,而一些事件在恢复阶段促进了rna -蛋白凝聚体的形成。通过位点诱变、抑制O-GlcNAc转移酶和荧光显微镜,我们验证了O-GlcNAc酰化调节YTHDF3和NUFIP2生物凝聚物的形成。这项工作促进了我们对蛋白质o - glcn酰化的功能及其在生物分子凝聚物形成中的作用的理解。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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