RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
Cell Stem Cell. 2022 Jul 7;29(7):1119-1134.e7. doi: 10.1016/j.stem.2022.06.004.
Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.
造血干细胞（HSCs）会调整其代谢以维持和增殖；然而，其具体机制尚不完全清楚。在这里，我们证明了稳态 HSCs 具有较高的氨基酸（AA）分解代谢活性，以降低细胞内 AA 水平，从而激活 GCN2-eIF2α 轴，这是一种抑制蛋白质合成的检查点，以限制维持所需的蛋白质合成。此外，在增殖条件下，HSCs 增强线粒体氧化磷酸化（OXPHOS）以产生更多的能量，但降低 AA 分解代谢以积累细胞内 AA，从而使 GCN2-eIF2α 轴失活以增加蛋白质合成，并伴有蛋白毒性应激。重要的是，GCN2 的缺失会损害 HSC 在重建造血和再生中的功能。在机制上，GCN2 可维持蛋白质稳态并抑制 Src 介导的 AKT 激活，从而抑制 HSCs 中的线粒体 OXPHOS。此外，糖酵解代谢物 NAD 前体烟酰胺核糖（NR）可加速 AA 分解代谢以激活 GCN2 并维持 HSCs 的长期功能。总的来说，我们的研究揭示了代谢改变与 HSCs 中在稳态和增殖过程中翻译控制之间的直接联系。
