Sin1-mTORC2 Suppresses rag and il7r Gene Expression through Akt2 in B Cells

SummaryMammalian target of rapamycin (mTOR) is an important mediator of phosphoinositol-3-kinase (PI3K) signaling. PI3K signaling regulates B cell development, homeostasis, and immune responses. However, the function and molecular mechanism of mTOR-mediated PI3K signaling in B cells has not been fully elucidated. Here we show that Sin1, an essential component of mTOR complex 2 (mTORC2), regulates B cell development. Sin1 deficiency results in increased IL-7 receptor (il7r) and RAG recombinase (rag1 and rag2) gene expression, leading to enhanced pro-B cell survival and augmented V(D)J recombinase activity. We further show that Akt2 specifically mediates the Sin1-mTORC2 dependent suppression of il7r and rag gene expression in B cells by regulating FoxO1 phosphorylation. Finally, we demonstrate that the mTOR inhibitor rapamycin induces rag expression and promotes V(D)J recombination in B cells. Our study reveals that the Sin1/mTORC2-Akt2 signaling axis is a key regulator of FoxO1 transcriptional activity in B cells.

Graphical AbstractFigure optionsDownload high-quality image (180 K)Download as PowerPoint slideHighlights
► Sin1 maintains mTORC2 integrity and regulates B cell development
► Sin1-mTORC2 utilizes Akt2 but not Akt1 to suppress il7r and rag gene expression
► Akt HM site phosphorylation is required to suppress FoxO1 target gene expression
► Rapamycin inhibits mTORC2 and promotes rag gene expression in B cells