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Cell Metab. 2018 Feb 6;27(2):393-403.e4. doi: 10.1016/j.cmet.2017.12.007. Epub 2018 Jan 11.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: emilywang@ucsd.edu.
4
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: baltimo@caltech.edu.

Abstract

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.

KEYWORDS:

B cells; antibody production; glutamine metabolism; glycolysis; let-7

PMID:
29337138
DOI:
10.1016/j.cmet.2017.12.007
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