Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis.
Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis.
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DOI：
10.1084/jem.20161855
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发表时间：
2017-09-04
期刊：
影响因子：
--
通讯作者：
Chi H
中科院分区：
文献类型：
--
作者：
Karmaus PWF;Herrada AA;Guy C;Neale G;Dhungana Y;Long L;Vogel P;Avila J;Clish CB;Chi H
Karmaus等人表明雷帕霉素复合物1（mTORC 1）信号传导的机制靶标的丧失损害骨髓生成。M-CSF依赖性骨髓生成需要mTORC 1信号传导和合成代谢，这反过来又促进M-CSFR和转录因子PU. 1和IRF 8的表达，从而构成骨髓生成的前馈回路。在稳态周转和免疫损伤过程中，骨髓生成对于成熟骨髓细胞的生成是必要的;然而，这一过程的代谢要求仍然不清楚。在这里，我们证明了骨髓生成，包括单核细胞和巨噬细胞的分化，需要雷帕霉素复合物1（mTORC 1）信号和合成代谢的机制目标。mTORC 1的缺失在稳态下损害骨髓生成，并抑制对单核细胞增生李斯特菌感染的先天免疫应答。用巨噬细胞集落刺激因子（M-CSF）刺激造血祖细胞导致mTORC 1依赖性合成代谢，这反过来促进M-CSF受体和转录因子PU. 1和IRF 8的表达，从而构成骨髓生成的前馈回路。mTORC 1参与葡萄糖代谢，并在M-CSF刺激后启动涉及Myc激活和甾醇生物合成的转录程序。葡萄糖代谢的紊乱或Myc功能或固醇生物合成的破坏损害了髓样分化。综合代谢组学和基因组分析进一步确定了一碳代谢作为mTORC 1依赖性骨髓生成的中心节点。因此，mTORC 1信号传导和代谢重编程之间的相互作用是M-CSF诱导的骨髓生成的基础。
Karmaus et al. show that loss of mechanistic target of rapamycin complex 1 (mTORC1) signaling impairs myelopoiesis. M-CSF–dependent myelopoiesis requires mTORC1 signaling and anabolic metabolism, which in turn promote expression of M-CSFR and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF–induced myelopoiesis.
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DOI：
10.1084/jem.20050075
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dakic A;Metcalf D;Di Rago L;Mifsud S;Wu L;Nutt SL
通讯作者：
Nutt SL
DOI：
10.1084/jem.20160800
发表时间：
2016-10-17
期刊：
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DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
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影响因子：
20.3
作者：
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通讯作者：
Stanley, ER
影响因子：
64.8
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Kotzin, Jonathan J.;Spencer, Sean P.;McCright, Sam J.;Kumar, Dinesh B. Uthaya;Collet, Magalie A.;Mowel, Walter K.;Elliott, Ellen N.;Uyar, Asli;Makiya, Michelle A.;Dunagin, Margaret C.;Harman, Christian C. D.;Virtue, Anthony T.;Zhu, Stella;Bailis, Will;Stein, Judith;Hughes, Cynthia;Raj, Arjun;Wherry, E. John;Goff, Loyal A.;Klion, Amy D.;Rinn, John L.;Williams, Adam;Flavell, Richard A.;Henao-Mejia, Jorge
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Henao-Mejia, Jorge