中山大学赵萌课题组发现，氨基酸分解作用通过GCN2-eIF2α轴调节造血干细胞的蛋白稳态。这一研究成果发表在2022年7月7日出版的国际学术期刊《细胞—干细胞》上。

研究人员证明了稳定的造血干细胞表现出高氨基酸（AA）分解，从而减少细胞AA水平，这激活了GCN2-eIF2α轴，这是一个蛋白质合成抑制检查点，进而抑制蛋白质的合成来维持。此外，在增殖条件下，造血干细胞增强线粒体氧化磷酸化（OXPHOS）来获得更高的能量生产，但减少AA分解来积累细胞中的AA，这使GCN2-eIF2α轴失活来增加蛋白质合成，并与蛋白质毒性压力相联系。重要的是，GCN2的缺失损害了造血干细胞的再增殖和再生功能。

从机制上讲，GCN2维持了蛋白稳定，并抑制了Src介导的AKT激活，从而抑制了造血干细胞中的线粒体OXPHOS。此外，糖酵解代谢物，NAD⁺前体烟酰胺核苷（NR）加速了AA的分解，从而激活GCN2并维持造血干细胞的长期功能。总的来说，这项研究发现了造血干细胞在平衡和增殖过程中的代谢改变和翻译控制之间的直接联系。

据了解，造血干细胞适应其代谢以维持和增殖；然而，其机制仍不完全了解。

附：英文原文

Title: Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis

Author: Changzheng Li, Binghuo Wu, Yishan Li, Jie Chen, Zhitao Ye, Xiaobin Tian, Jin Wang, Xi Xu, Shuai Pan, Yucan Zheng, Xiongwei Cai, Linjia Jiang, Meng Zhao

Issue&Volume: 2022/07/07

Abstract: Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation;however, the mechanism remains incompletely understood. Here, we demonstrated thathomeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels,which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint torestrain protein synthesis for maintenance. Furthermore, upon proliferation conditions,HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy productionbut decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2αaxis 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 repressmitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD+ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2and sustain the long-term function of HSCs. Overall, our study uncovered direct linksbetween metabolic alterations and translation control in HSCs during homeostasis andproliferation.

DOI: 10.1016/j.stem.2022.06.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00253-3