Rictor is required for early B cell development in bone marrow.
Rictor is required for early B cell development in bone marrow.
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Rictor 是骨髓早期 B 细胞发育所必需的
DOI：
10.1371/journal.pone.0103970
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yuan W
中科院分区：
文献类型：
--
作者：
Zhang Y;Hu T;Hua C;Gu J;Zhang L;Hao S;Liang H;Wang X;Wang W;Xu J;Liu H;Liu B;Cheng T;Yuan W
早期B细胞的发育代表了终末分化过程的范例，所述早期B细胞在骨髓（BM）中的一系列充分表征的阶段中由造血干细胞（HSC）产生。Akt主要由PDK 1在Thr 308处的磷酸化和mTORC 2在Ser 473处的磷酸化调节，并且Akt信号传导在造血中起关键作用。然而，mTORC 2在早期B细胞发育中的作用仍然知之甚少。在这项研究中，我们研究了mTORC 2的功能作用，专门删除一个组成部分，Rictor，在造血系统。我们证明，Rictor的缺失诱导骨髓B细胞中FoxO 1和Rag-1蛋白的异常增加，并且这种增加伴随着外周血（PB）和脾脏中B细胞丰度的显著降低，表明成年小鼠骨髓中早期B细胞的发育受损。骨髓移植试验表明，由Rictor缺失诱导的B细胞分化缺陷不受骨髓微环境的影响，从而表明细胞内在机制。此外，FoxO 1在Rictor缺失的HSC和造血祖细胞（HPC）中的敲低促进受体小鼠BM中B细胞的成熟。此外，我们发现，雷帕霉素（mTORC 1抑制剂）治疗加重了PB和BM中B细胞发育的缺陷。综上所述，我们的结果提供了进一步的证据，Rictor调节早期B细胞的发展，在细胞内的方式通过修改FoxO 1和Rag-1的表达。
The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1.
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