Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway
Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway
复制标题
赖氨酸2-羟基异丁酰化途径的调控元件概况
DOI：
10.1038/cr.2017.149
复制
发表时间：
2018-01-01
期刊：
影响因子：
44.1
通讯作者：
Zhao, Yingming
中科院分区：
文献类型：
--
作者：
Huang, He;Luo, Zhouqing;Zhao, Yingming
短链脂肪酸及其相应的酰基辅酶A位于代谢途径的十字路口，在多种细胞过程中发挥重要作用。它们也是蛋白质翻译后赖氨酸酰化修饰的前体。一个值得注意的例子是新鉴定的赖氨酸2-羟基异丁酰化（K-hib），其衍生自2-羟基异丁酸和2-羟基异丁酰-CoA。组蛋白K-hib已被证明与生精细胞中的活性基因表达相关。然而，调节这种翻译后赖氨酸酰化途径的关键元件仍然未知。这阻碍了表征这种修饰发挥其生物学功能的机制。在这里，我们表明，Esa 1 p在芽殖酵母和它的同源Tip 60在人类可以添加K-hib底物蛋白在体外和体内。此外，我们已经确定HDAC 2和HDAC 3是去除K-hib的主要酶。此外，我们报告了第一个全球性的哺乳动物细胞中的K-hib蛋白质组，确定6548 K-hib位点上的1725底物蛋白。因此，我们的研究发现了组蛋白K-hib标记的“写入器”和“擦除器”，以及主要的K-hib蛋白底物。这些结果不仅说明了这种新的赖氨酸酰化途径的景观，但也开辟了新的途径，研究与此相关的细胞代谢产物的各种功能。
Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation (K-hib) that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone K-hib has been shown to be associated with active gene expression in spermatogenic cells. However, the key elements that regulate this post-translational lysine acylation pathway remain unknown. This has hindered characterization of the mechanisms by which this modification exerts its biological functions. Here we show that Esa1p in budding yeast and its homologue Tip60 in human could add K-hib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major enzymes to remove K-hib. Moreover, we report the first global profiling of K-hib proteome in mammalian cells, identifying 6 548 K-hib sites on 1 725 substrate proteins. Our study has thus discovered both the "writers" and "erasers" for histone K-hib marks, and major K-hib protein substrates. These results not only illustrate the landscape of this new lysine acylation pathway, but also open new avenues for studying diverse functions of cellular metabolites associated with this pathway.