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Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients.
Cell Metabolism ( IF 29.0 ) Pub Date : 2018-Feb-06 , DOI: 10.1016/j.cmet.2017.12.007
Shuai Jiang , Wei Yan , Shizhen Emily Wang , David Baltimore

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.

中文翻译:

Let-7通过限制必需营养素的供应来抑制B细胞活化。

控制必需的细胞外营养物(葡萄糖和谷氨酰胺)的摄取和利用是B细胞活化的重要方面。Let-7是已知参与代谢控制的一系列microRNA。在这里,我们采用了几种工程化的小鼠模型,包括B细胞特定的Lin28a或let-7a-1 / let-7d / let-7f-1簇(let-7adf)的过表达以及单个let-7簇的敲除,以显示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抗体的产生。在该簇中let-7的过度表达和缺失均导致改变的TI-IgM产生。从机理上讲,let-7adf抑制了关键营养素(包括葡萄糖和谷氨酰胺)的获取和利用,通过直接靶向己糖激酶2(Hk2)并抑制谷氨酰胺转运蛋白Slc1a5和关键降解酶谷氨酰胺酶(Gls),这是一种通过调节c-Myc介导的机制。我们的结果表明let-7adf作为B细胞抗体产生的“代谢制动”具有新的作用。
更新日期:2018-01-11
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