Histone deacetylase 6 (HDAC6) is upregulated in a variety of tumor cell lines and has been linked to many cellular processes, such as cell signaling, protein degradation, cell survival, and cell motility. HDAC6 is an enzyme that deacetylates the acetyllysine residues of protein substrates, and the discovery of HDAC6 substrates, including tubulin, has revealed many roles of HDAC6 in cell biology. Unfortunately, among the wide variety of acetylated proteins in the cell, only a few are verified as HDAC6 substrates, which limits the full characterization of HDAC6 cellular functions. Substrate trapping mutants were recently established as a tool to discover unanticipated substrates of histone deacetylase 1 (HDAC1). In this study, we applied the trapping approach to identify potential HDAC6 substrates. Among the high confidence protein hits after trapping, protein arginine methyl transferase 5 (PRMT5) was successfully validated as a novel HDAC6 substrate. PRMT5 acetylation enhanced its methyltransferase activity and symmetrical dimethylation of downstream substrates, revealing possible crosstalk between acetylation and methylation. Substrate trapping represents a powerful, systematic, and unbiased approach to discover substrates of HDAC6.

中文翻译：

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使用基于蛋白质组学的底物捕获发现 HDAC6 底物：HDAC6 使 PRMT5 去乙酰化以影响甲基转移酶活性

组蛋白去乙酰化酶 6 (HDAC6) 在多种肿瘤细胞系中上调，并与许多细胞过程有关，例如细胞信号传导、蛋白质降解、细胞存活和细胞运动。HDAC6是一种使蛋白质底物的乙酰赖氨酸残基去乙酰化的酶，包括微管蛋白在内的HDAC6底物的发现揭示了HDAC6在细胞生物学中的许多作用。不幸的是，在细胞中种类繁多的乙酰化蛋白中，只有少数被证实为 HDAC6 底物，这限制了 HDAC6 细胞功能的全面表征。最近建立了底物捕获突变体作为发现组蛋白脱乙酰酶 1 (HDAC1) 的意外底物的工具。在这项研究中，我们应用诱捕方法来识别潜在的 HDAC6 底物。在捕获后的高置信度蛋白质命中中，蛋白质精氨酸甲基转移酶 5 (PRMT5) 被成功验证为新型 HDAC6 底物。PRMT5 乙酰化增强了其甲基转移酶活性和下游底物的对称二甲基化，揭示了乙酰化和甲基化之间可能的串扰。底物捕获代表了一种强大、系统和公正的方法来发现 HDAC6 的底物。