Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells
Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells
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DOI：
10.1016/j.bbrc.2017.11.140
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发表时间：
2018-01-01
影响因子：
3.1
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
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作者：
Peng, Hui;Kasada, Atsuo;Hirao, Atsushi
哺乳动物雷帕霉素靶蛋白（mTOR）复合物1（mTORC 1）可以感知细胞的能量状态和营养素和生长因子的环境水平。作为响应，mTORC 1介导控制蛋白质翻译和细胞代谢的信号传导。虽然mTORC 1在造血中起着关键作用，但仍不清楚在体内造血干细胞（HSC）维持的背景下哪些上游刺激物调节mTORC 1活性。在这项研究中，我们研究了Rheb的功能，Rheb是由PI 3 K-AKT-TSC轴控制的mTORC 1活性的关键调节剂，在稳态小鼠的HSC维持和移植后HSC衍生的造血中。与Raptor缺失导致的严重造血功能障碍相反，成年小鼠中的Rheb缺乏没有表现出明显的造血功能衰竭，Raptor缺失完全灭活mTORC 1。缺乏Rheb导致骨髓细胞异常，但对受辐射损伤的小鼠的造血再生没有影响。如前所述，Rheb缺乏导致移植后HSC衍生的造血功能缺陷。然而，虽然Raptor对于HSC在体内的竞争力是必不可少的，但是Rheb对于在生理条件下的HSC维持是不可或缺的，这表明PI 3 K-AKT-TSC途径不有助于mTORC 1活性以维持稳态的HSC自我更新活性。因此，各种调控元件，冲击上游mTORC 1激活途径的差异所需的HSC体内稳态。(C)2017爱思唯尔公司All rights reserved.
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1 mediates signaling that controls protein translation and cellular metabolism. Although mTORC1 plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1 activity in the context of hematopoietic stem cells (HSC) maintenance in vivo. In this study, we investigated the function of Rheb, a critical regulator of mTORC1 activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation. In contrast to the severe hematopoietic dysfunction caused by Raptor deletion, which completely inactivates mTORC1, Rheb deficiency in adult mice did not show remarkable hematopoietic failure. Lack of Rheb caused abnormalities in myeloid cells but did not have impact on hematopoietic regeneration in mice subjected to injury by irradiation. As previously reported, Rheb deficiency resulted in defective HSC-derived hematopoiesis post-transplantation. However, while Raptor is essential for HSC competitiveness in vivo, Rheb is dispensable for HSC maintenance under physiological conditions, indicating that the PI3K-AKT-TSC pathway does not contribute to mTORC1 activity for sustaining HSC self-renewal activity at steady-state. Thus, the various regulatory elements that impinge upstream of mTORC1 activation pathways are differentially required for HSC homeostasis in vivo. (C) 2017 Elsevier Inc. All rights reserved.