4 years ago

mTOR-Bach2 cascade controls cell cycle and class switch recombination during B cell differentiation.

Sax, Muto, Igarashi, Matsumoto, Tamahara, Kato, Koseki, Ochiai
The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. Firstly, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Secondly, mTORC complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, Ccnd3 gene encoding Cyclin D3 was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055 mTOR inhibitor increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.

Publisher URL: http://doi.org/10.1128/MCB.00418-17

DOI: 10.1128/MCB.00418-17

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