Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.
Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.
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DOI：
10.1126/sciadv.abi6696
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发表时间：
2022-01-21
期刊：
影响因子：
13.6
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Moreno-Yruela C;Zhang D;Wei W;Bæk M;Liu W;Gao J;Danková D;Nielsen AL;Bolding JE;Yang L;Jameson ST;Wong J;Olsen CA;Zhao Y
赖氨酸L-乳酰化[K(L - la)]是一种在高糖酵解条件下（如沃伯格效应）新发现的组蛋白标记。K(L - la)所具有的功能与被广泛研究的组蛋白乙酰化不同。虽然K(L - la)可由乙酰转移酶p300引入，但组蛋白去乳酰化酶却一直不为人知。在此，我们报道了对锌离子和烟酰胺腺嘌呤二核苷酸依赖的组蛋白去乙酰化酶（HDACs）切割ε - N - L -乳酰赖氨酸标记能力的系统性评估。我们的筛选鉴定出HDAC1 - 3和SIRT1 - 3在体外为去乳酰化酶。HDAC1 - 3不仅对K(L - la)，而且对K(D - la)以及多种短链酰基修饰都表现出较强的活性。我们进一步证实了HDAC1和HDAC3在细胞中的去L -乳酰化酶活性。总之，这些数据表明组蛋白乳酰化是由调节酶而非自发化学反应来添加和去除的。因此，我们的结果是朝着全面阐明该途径调节元件特性迈出的重要一步。
去乙酰化酶从赖氨酸侧链切割乳酰修饰，表明组蛋白乳酰化受到积极调控。
Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε-N-L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements. Deacetylase enzymes cleave lactyl modifications from lysine side chains, showing that histone lactylation is actively regulated.
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