Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Metab. 2018 Feb 6;27(2):393-403.e4. doi: 10.1016/j.cmet.2017.12.007. Epub 2018 Jan 11.
The control of uptake and utilization of necessary extracellular nutrients-glucose and glutamine-is an important aspect of B cell activation. Let-7 is a family of microRNAs known to be involved in metabolic control. Here, we employed several engineered mouse models, including B cell-specific overexpression of Lin28a or the let-7a-1/let-7d/let-7f-1 cluster (let-7adf) and knockout of individual let-7 clusters to show that let-7adf specifically inhibits T cell-independent (TI) antigen-induced immunoglobulin (Ig)M antibody production. Both overexpression and deletion of let-7 in this cluster leads to altered TI-IgM production. Mechanistically, let-7adf suppresses the acquisition and utilization of key nutrients, including glucose and glutamine, through directly targeting hexokinase 2 (Hk2) and by repressing a glutamine transporter Slc1a5 and a key degradation enzyme, glutaminase (Gls), a mechanism mediated by regulation of c-Myc. Our results suggest a novel role of let-7adf as a "metabolic brake" on B cell antibody production.
控制必需的细胞外营养物质（葡萄糖和谷氨酰胺）的摄取和利用是 B 细胞激活的一个重要方面。Let-7 是一类已知参与代谢控制的 microRNA。在这里，我们利用几种工程化的小鼠模型，包括 B 细胞特异性过表达 Lin28a 或 let-7a-1/let-7d/let-7f-1 簇（let-7adf）以及敲除单个 let-7 簇，表明 let-7adf 特异性抑制 T 细胞非依赖性（TI）抗原诱导的免疫球蛋白（Ig）M 抗体产生。该簇中 let-7 的过表达和缺失都会导致 TI-IgM 产生的改变。在机制上，let-7adf 通过直接靶向己糖激酶 2（Hk2）和抑制谷氨酰胺转运蛋白 Slc1a5 以及关键降解酶谷氨酰胺酶（Gls）来抑制关键营养物质（包括葡萄糖和谷氨酰胺）的摄取和利用，这是通过调节 c-Myc 介导的机制实现的。我们的研究结果表明，let-7adf 在 B 细胞抗体产生中具有作为“代谢制动器”的新作用。
