Sin Yi-Cheng, Abernathy Breann, Yuan Zuo-Fei, Heier Jason L, Gonzalez Justin E, Parker Laurie L, Mashek Douglas G, Chen Yue
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, USA.
Bioinformatics and Computational Biology Program, University of Minnesota Twin Cities, Minneapolis, MN, USA.
Sci Adv. 2025 May 30;11(22):eadv1071. doi: 10.1126/sciadv.adv1071.
Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.
环境因素可能通过组蛋白和转录因子的表观遗传修饰来影响基因表达。在此，我们报告，常见食品防腐剂山梨酸盐的细胞摄取会在哺乳动物细胞和组织中诱导赖氨酸山梨酰化（Ksor），这是由I类组蛋白去乙酰化酶（HDAC1 - 3）的非经典活性介导的。我们证明，HDAC1 - 3在体外和细胞中摄取山梨酸盐时催化山梨酰化，在没有山梨酸盐的情况下催化去山梨酰化。小鼠肝脏中山梨酸盐的摄取显著诱导组蛋白Ksor，这与炎症反应基因表达的降低相关。因此，在脂多糖（LPS）刺激下，巨噬细胞RAW264.7细胞中的山梨酸盐处理剂量依赖性地下调促炎基因表达和一氧化氮产生。蛋白质组学分析确定NF-κB复合物的一个组成部分RelA及其相互作用蛋白为真正的Ksor靶点，并且山梨酸盐处理显著降低了RAW264.7细胞中对LPS刺激的NF-κB转录活性。总之，我们的研究证明了山梨酸盐摄取在调节表观遗传组蛋白修饰和炎症基因表达中的一种非经典机制。
