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  3. Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis

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

  • Cell Stem Cell. 2022 Jul 7;29(7):1119-1134.e7. doi: 10.1016/j.stem.2022.06.004.
Changzheng Li 1,  Binghuo Wu 1,  Yishan Li 1,  Jie Chen 2,  Zhitao Ye 3,  Xiaobin Tian 3,  Jin Wang 3,  Xi Xu 2,  Shuai Pan 3,  Yucan Zheng 3,  Xiongwei Cai 4,  Linjia Jiang 2,  Meng Zhao 5
Affiliations

Affiliations

  • 1 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.
  • 2 RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
  • 3 Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
  • 4 Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing 404100, China.
  • 5 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. Electronic address: zhaom38@mail.sysu.edu.cn.
PMID: 35803229 DOI: 10.1016/j.stem.2022.06.004
Abstract

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.

Keywords

GCN2; amino acid; hematopoietic stem cells; metabolism; nicotinamide riboside; oxidative phosphorylation; protein translation; proteostasis.

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