A bioorthogonal chemical reporter for the detection and identification of protein lactylation,Chemical Science

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A bioorthogonal chemical reporter for the detection and identification of protein lactylation
Chemical Science ( IF 7.6 ) Pub Date : 2022-04-26 , DOI: 10.1039/d2sc00918h
Yanan Sun ₁ , Yanchi Chen ₁ , Tao Peng _{1,

2}

Affiliation

L-Lactylation is a recently discovered post-translational modification occurring on histone lysine residues to regulate gene expression. However, the substrate scope of lactylation, especially that in non-histone proteins, remains unknown, largely due to the limitations of current methods for analyzing lactylated proteins. Herein, we report an alkynyl-functionalized bioorthogonal chemical reporter, YnLac, for the detection and identification of protein lactylation in mammalian cells. Our in-gel fluorescence and chemical proteomic analyses show that YnLac is metabolically incorporated into lactylated proteins and directly labels known lactylated lysines of histones. We further apply YnLac to the proteome-wide profiling of lactylation, revealing many novel modification sites in non-histone proteins for the first time. Moreover, we demonstrate that lactylation of a newly identified substrate protein PARP1 regulates its ADP-ribosylation activity. Our study thus provides a powerful chemical tool for characterizing protein lactylation and greatly expands our understanding of substrate proteins and functions of this new modification.

中文翻译：

用于检测和鉴定蛋白质乳酸化的生物正交化学报告器

大号-乳酸化是最近发现的一种翻译后修饰，发生在组蛋白赖氨酸残基上以调节基因表达。然而，乳酸化的底物范围，尤其是非组蛋白中的底物范围，仍然未知，这主要是由于目前分析乳酸化蛋白质的方法的局限性。在这里，我们报告了一种炔基功能化的生物正交化学报告基因 YnLac，用于检测和鉴定哺乳动物细胞中的蛋白质乳酸化。我们的凝胶内荧光和化学蛋白质组学分析表明，YnLac 在代谢上并入乳酸化蛋白质并直接标记已知的组蛋白乳酸化赖氨酸。我们进一步将 YnLac 应用于蛋白质组范围内的乳酸化分析，首次揭示了非组蛋白中的许多新修饰位点。而且，我们证明了新发现的底物蛋白 PARP1 的乳酸化调节其 ADP 核糖基化活性。因此，我们的研究为表征蛋白质乳酸化提供了一种强大的化学工具，并极大地扩展了我们对底物蛋白和这种新修饰的功能的理解。

更新日期：2022-04-26

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