Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Drug Innovation Research Center, Daiichi University of Pharmacy, Fukuoka, Japan.
Genes Cells. 2020 Apr;25(4):270-278. doi: 10.1111/gtc.12758. Epub 2020 Mar 3.
The expression levels of many cell-surface proteins vary with the time of day. Glycoprotein 2 (Gp2), specifically expressed on the apical surface of M cells in Peyer's patches, functions as a transcytotic receptor for mucosal antigens. We report that cAMP response element-binding protein (CREB) regulates the transcription of the Gp2 gene, thereby generating the circadian change in its expression in mouse Peyer's patches. The transcytotic receptor activity of Gp2 was increased during the dark phase when the Gp2 protein abundance increased. Rhythmic expression of clock gene mRNA was observed in mouse Peyer's patches, and expression levels of Gp2 mRNA also exhibited circadian oscillation, with peak levels during the early dark phase. The promoter region of the mouse Gp2 gene contains several cAMP response elements (CREs). Chromatin immunoprecipitation assays revealed that CREB bound to the CREs in the Gp2 gene in Peyer's patches. Forskolin, which promotes CREB phosphorylation, increased the transcription of the Gp2 gene in Peyer's patches. As phosphorylation of CREB protein was increased when Gp2 gene transcription was activated, CREB may regulate the rhythmic expression of Gp2 mRNA in Peyer's patches. These findings suggest that intestinal immunity is controlled by the circadian clock system.
许多细胞表面蛋白的表达水平随时间变化。糖蛋白 2（Gp2）特异性表达于派氏集合淋巴结的 M 细胞顶表面，作为黏膜抗原的转胞吞受体发挥作用。我们报道 cAMP 反应元件结合蛋白（CREB）调节 Gp2 基因的转录，从而使其在小鼠派氏集合淋巴结中的表达产生昼夜变化。当 Gp2 蛋白丰度增加时，Gp2 的转胞吞受体活性在暗期增加。时钟基因 mRNA 在小鼠派氏集合淋巴结中呈现节律性表达，Gp2 mRNA 的表达水平也表现出昼夜振荡，在暗期早期达到峰值。小鼠 Gp2 基因的启动子区域含有几个 cAMP 反应元件（CREs）。染色质免疫沉淀分析显示，CREB 在派氏集合淋巴结中的 Gp2 基因上结合 CREs。促进 CREB 磷酸化的佛司可林增加了派氏集合淋巴结中 Gp2 基因的转录。当 Gp2 基因转录被激活时，CREB 蛋白的磷酸化增加，因此 CREB 可能调节派氏集合淋巴结中 Gp2 mRNA 的节律性表达。这些发现表明肠道免疫受昼夜节律系统的控制。
