Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504, Japan.
Division of Food & Health Sciences, Department of Environmental and Symbiotic Sciences, Faculty of Environmental and Symbiotic Sciences, Prefectural University of Kumamoto, Kumamoto, 862-8502, Japan.
Commun Biol. 2022 Jul 13;5(1):639. doi: 10.1038/s42003-022-03577-5.
Glucosylceramide is the primary molecule of glycosphingolipids, and its metabolic regulation is crucial for life. Defects in the catabolizing enzyme, glucocerebrosidase (GCase), cause a lysosomal storage disorder known as Gaucher disease. However, the genetic regulation of GCase has not been fully understood. Here we show the redefined structure of the GCase coding gene (GBA), and clarify the regulatory mechanisms of its transcription and translation. First, alternative uses of the two GBA gene promoters were identified in fibroblasts and HL60-derived macrophages. Intriguingly, both GBA transcripts and GCase activities were induced in macrophages but not in neutrophils. Second, we observed cap-independent translation occurs via unique internal ribosome entry site activities in first promoter-driven GBA transcripts. Third, the reciprocal expression was observed in GBA and miR22-3p versus GBAP1 transcripts before and after HL60-induced macrophage differentiation. Nevertheless, these findings clearly demonstrate novel cell-type-specific GBA gene expression regulatory mechanisms, providing new insights into GCase biology.
葡萄糖脑苷脂是糖脂的主要分子，其代谢调节对生命至关重要。分解酶葡萄糖脑苷脂酶（GCase）的缺陷会导致溶酶体贮积症，即戈谢病。然而，GCase 的遗传调控尚未完全阐明。在这里，我们重新定义了 GCase 编码基因（GBA）的结构，并阐明了其转录和翻译的调控机制。首先，我们在成纤维细胞和 HL60 衍生的巨噬细胞中鉴定了两个 GBA 基因启动子的交替使用。有趣的是，两种 GBA 转录本和 GCase 活性都在巨噬细胞中诱导，但在中性粒细胞中没有诱导。其次，我们观察到第一个启动子驱动的 GBA 转录本中存在帽非依赖性翻译，通过独特的内部核糖体进入位点活性。第三，在 HL60 诱导的巨噬细胞分化前后，GBA 和 miR22-3p 与 GBAP1 转录本之间存在相互表达。然而，这些发现清楚地表明了新型细胞特异性 GBA 基因表达调控机制，为 GCase 生物学提供了新的见解。
