Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Publication date: Available online 11 January 2018
Source:Cell Metabolism
Author(s): 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.

Graphical abstract

Teaser

Activated B cells require nutrients to build biomass and function physiologically. Jiang et al. show that the microRNA let-7adf cluster acts as a "metabolic brake" in activated B cells by suppressing T cell-independent antigen-induced IgM antibody production. Mechanistically, let-7adf regulates uptake and utilization of key nutrients including glucose and glutamine.


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