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The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation.
Toru Tamahara1,2, Kyoko Ochiai3, Akihiko Muto1
1Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Molecular and Cellular Biology
|October 11, 2017
Summary
The mammalian target of rapamycin (mTOR) pathway regulates Bach2, a key immune regulator, impacting B cell differentiation and immunoglobulin gene rearrangement. This study reveals mTOR
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Bach2 is a transcription factor crucial for adaptive and innate immunity.
- Its regulation by cytokine and antigen signaling is poorly understood.
- Bach2 influences antibody class switching and regulatory T cell development.
Purpose of the Study:
- To elucidate the molecular mechanisms controlling Bach2.
- To investigate the role of mammalian target of rapamycin (mTOR) in Bach2 regulation during B cell differentiation.
- To identify new Bach2 targets and their function in B cell development.
Main Methods:
- Utilized expression profiling and chromatin immunoprecipitation assays.
- Investigated Bach2 regulation by mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
- Analyzed B cell differentiation in Bach2-deficient mice and the effects of an mTOR inhibitor (AZD8055).
Main Results:
- mTORC1 inhibits Bach2 protein nuclear accumulation and stability.
- mTORC2 inhibits FoxO1, reducing Bach2 mRNA expression.
- Identified Ccnd3 (cyclin D3) as a direct Bach2 target, crucial for cell cycle regulation.
- Bach2 deficiency disrupts cell cycle arrest in pre-B and mature B cells.
- mTOR inhibition enhances class switch recombination in wild-type but not Bach2-deficient B cells.
Conclusions:
- The mTOR-Bach2 signaling cascade is critical for regulating B cell cycle arrest.
- This pathway also plays a role in immunoglobulin gene rearrangement.
- Bach2 acts as a key mediator linking mTOR signaling to proper B cell development and function.