Zhang Ran, Bons Joanna, Scheidemantle Grace, Liu Xiaojing, Bielska Olga, Carrico Chris, Rose Jacob, Heckenbach Indra, Scheibye-Knudsen Morten, Schilling Birgit, Verdin Eric
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
iScience. 2023 Feb 13;26(3):106193. doi: 10.1016/j.isci.2023.106193. eCollection 2023 Mar 17.
The posttranslational modification lysine malonylation is found in many proteins, including histones. However, it remains unclear whether histone malonylation is regulated or functionally relevant. Here, we report that availability of malonyl-co-enzyme A (malonyl-CoA), an endogenous malonyl donor, affects lysine malonylation, and that the deacylase SIRT5 selectively reduces malonylation of histones. To determine if histone malonylation is enzymatically catalyzed, we knocked down each of the 22 lysine acetyltransferases (KATs) to test their malonyltransferase potential. KAT2A knockdown in particular reduced histone malonylation levels. By mass spectrometry, H2B_K5 was highly malonylated and regulated by SIRT5 in mouse brain and liver. Acetyl-CoA carboxylase (ACC), the malonyl-CoA producing enzyme, was partly localized in the nucleolus, and histone malonylation increased nucleolar area and ribosomal RNA expression. Levels of global lysine malonylation and ACC expression were higher in older mouse brains than younger mice. These experiments highlight the role of histone malonylation in ribosomal gene expression.
翻译后修饰赖氨酸丙二酰化存在于包括组蛋白在内的多种蛋白质中。然而，组蛋白丙二酰化是否受到调控或具有功能相关性仍不清楚。在此，我们报告内源性丙二酰供体丙二酰辅酶A（丙二酰-CoA）的可用性会影响赖氨酸丙二酰化，并且去酰基酶SIRT5可选择性降低组蛋白的丙二酰化。为了确定组蛋白丙二酰化是否由酶催化，我们敲低了22种赖氨酸乙酰转移酶（KAT）中的每一种，以测试它们的丙二酰转移酶潜力。特别是敲低KAT2A可降低组蛋白丙二酰化水平。通过质谱分析，在小鼠脑和肝脏中，H2B_K5高度丙二酰化且受SIRT5调控。丙二酰-CoA产生酶乙酰辅酶A羧化酶（ACC）部分定位于核仁，组蛋白丙二酰化增加了核仁面积和核糖体RNA表达。老年小鼠脑中全局赖氨酸丙二酰化水平和ACC表达高于年轻小鼠。这些实验突出了组蛋白丙二酰化在核糖体基因表达中的作用。
