Department of Medicine, the Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
J Biol Chem. 2011 Aug 12;286(32):28019-25. doi: 10.1074/jbc.M111.253385. Epub 2011 Jun 17.
The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) is a critical cytosolic enzyme needed for lung surfactant synthesis that catalyzes an acyltransferase reaction by adding a palmitate to the sn-2 position of lysophospholipids. Here we report that histone H4 protein is subject to palmitoylation catalyzed by Lpcat1 in a calcium-regulated manner. Cytosolic Lpcat1 was observed to shift into the nucleus in lung epithelia in response to exogenous Ca(2+). Nuclear Lpcat1 colocalizes with and binds to histone H4, where it catalyzes histone H4 palmitoylation. Mutagenesis studies demonstrated that Ser(47) within histone H4 serves as a putative acceptor site, indicative of Lpcat1-mediated O-palmitoylation. Lpcat1 knockdown or expression of a histone H4 Ser(47A) mutant protein in cells decreased cellular mRNA synthesis. These findings provide the first evidence of a protein substrate for Lpcat1 and reveal that histone lipidation may occur through its O-palmitoylation as a novel post-translational modification. This epigenetic modification regulates global gene transcriptional activity.
酰基辅酶 A：溶血磷脂酰胆碱酰基转移酶（Lpcat1）是一种关键的细胞质酶，对于肺表面活性剂的合成是必需的，它通过将棕榈酸添加到溶血磷脂的 sn-2 位置来催化酰基转移反应。在这里，我们报告组蛋白 H4 蛋白受到 Lpcat1 的棕榈酰化作用调控，这种棕榈酰化作用是钙调节的。在肺上皮细胞中，观察到细胞质 Lpcat1 响应外源性 Ca(2+)而转移到细胞核中。核 Lpcat1 与组蛋白 H4 共定位并与之结合，在那里它催化组蛋白 H4 的棕榈酰化。突变研究表明，组蛋白 H4 内的丝氨酸（Ser47）作为一个潜在的接受位点，表明 Lpcat1 介导的 O-棕榈酰化。细胞中 Lpcat1 的敲低或组蛋白 H4 Ser47A 突变蛋白的表达降低了细胞内的 mRNA 合成。这些发现提供了 Lpcat1 的第一个蛋白质底物的证据，并表明组蛋白脂质化可能通过其 O-棕榈酰化作为一种新的翻译后修饰发生。这种表观遗传修饰调节全局基因转录活性。
