HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine.
HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine.
复制标题
DOI：
10.1021/acschembio.6b00396
复制
发表时间：
2016-10-21
影响因子：
4
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Aramsangtienchai P;Spiegelman NA;He B;Miller SP;Dai L;Zhao Y;Lin H
组蛋白去乙酰化酶（HDAC）家族通过对组蛋白和非组蛋白上赖氨酸残基的去乙酰化作用调节多种生物学途径。哺乳动物有18种HDAC，分为四类。I类、II类和IV类是锌依赖型的，而III类是烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖型赖氨酸去乙酰化酶或沉默调节蛋白。HDAC8是I类HDAC家族成员，在体外已被证明与其他HDAC相比具有较低的去乙酰化活性。最近的研究表明，几种具有低去乙酰化酶活性的沉默调节蛋白实际上能更有效地水解其他酰基赖氨酸修饰。受此启发，我们使用多种不同的酰基赖氨酸肽测试了HDAC8的活性。通过筛选一组具有不同酰基赖氨酸修饰的肽，我们发现HDAC8能够催化从组蛋白H3肽（H3K9）的赖氨酸9上移除具有2 - 16个碳原子的酰基。有趣的是，HDAC8对辛酰基、十二酰基和肉豆蔻酰基赖氨酸的催化效率（kcat / Km）比其对乙酰基赖氨酸的催化效率高几倍。HDAC8对较大脂肪酰基的催化效率提高是由于其Km值低得多。用HDAC8特异性抑制剂PCI - 34051处理的T细胞白血病Jurkat细胞与对照处理相比，整体脂肪酰化程度增加。因此，HDAC8的去脂肪酰化活性可能具有生理相关性。这是首次关于具有去脂肪酰化活性的锌依赖型HDAC的报道，确定HDAC8的去脂肪酰化靶点将有助于进一步了解HDAC8的功能以及蛋白质赖氨酸脂肪酰化。
The histone deacetylase (HDAC) family regulates several biological pathways through the deacetylation of lysine residues on histone and non-histone proteins. Mammals have 18 HDACs that are classified into four classes. Class I, II, and IV are zinc-dependent while class III is nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase or sirtuins. HDAC8, a class I HDAC family member, has been shown to have low deacetylation activity compared to other HDACs in vitro. Recent studies showed that several sirtuins, with low deacetylase activities can actually hydrolyze other acyl lysine modifications more efficiently. Inspired by this, we tested the activity of HDAC8 using a variety of different acyl lysine peptides. Screening a panel of peptides with different acyl lysine modifications, we found that HDAC8 can catalyze the removal of acyl groups with 2-16 carbons from lysine 9 of the histone H3 peptide (H3K9). Interestingly, the catalytic efficiencies (kcat/Km) of HDAC8 on octanoyl, dodecanoyl, and myristoyl lysine are several folds better than that on acetyl lysine. The increased catalytic efficiencies of HDAC8 on larger fatty acyl groups are due to the much lower Km values. T-cell leukemia Jurkat cells treated with a HDAC8 specific inhibitor, PCI-34051, exhibited an increase in global fatty acylation compared to control treatment. Thus, the defatty-acylation activity of HDAC8 is likely physiologically relevant. This is the first report of a zinc-dependent HDAC with defatty-acylation activity and identification of HDAC8 defatty-acylation targets will help to further understand the function of HDAC8 and protein lysine fatty acylation.