2. Academic Validation
  3. Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis

Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis

  • Cell Discov. 2021 Oct 26;7(1):98. doi: 10.1038/s41421-021-00332-8.
Fan Zhang  # 1,  Qi-Yu Zeng  # 2,  Hao Xu  # 3,  Ai-Ning Xu  # 1,  Dian-Jia Liu 1 4,  Ning-Zhe Li 1 4,  Yi Chen 1,  Yi Jin 1,  Chun-Hui Xu 5,  Chang-Zhou Feng 1,  Yuan-Liang Zhang 1,  Dan Liu 1 6,  Na Liu 1 5,  Yin-Yin Xie 1,  Shan-He Yu 1,  Hao Yuan 1,  Kai Xue 1,  Jing-Yi Shi 1,  Ting Xi Liu 1 5,  Peng-Fei Xu 7,  Wei-Li Zhao 1,  Yi Zhou 8,  Lan Wang 5,  Qiu-Hua Huang 1,  Zhu Chen 1,  Sai-Juan Chen 9,  Xiao-Long Zhou 10,  Xiao-Jian Sun 11
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 5 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6 Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
  • 7 Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 8 Stem Cell Program, Hematology/Oncology Program at Children's Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 34697290 DOI: 10.1038/s41421-021-00332-8
Abstract

The amino acid response (AAR) and unfolded protein response (UPR) pathways converge on eIF2α phosphorylation, which is catalyzed by Gcn2 and PERK, respectively, under different stresses. This close interconnection makes it difficult to specify different functions of AAR and UPR. Here, we generated a zebrafish model in which loss of threonyl-tRNA synthetase (Tars) induces angiogenesis dependent on Tars aminoacylation activity. Comparative transcriptome analysis of the tars-mutant and wild-type embryos with/without Gcn2- or Perk-inhibition reveals that only Gcn2-mediated AAR is activated in the tars-mutants, whereas PERK functions predominantly in normal development. Mechanistic analysis shows that, while a considerable amount of eIF2α is normally phosphorylated by PERK, the loss of Tars causes an accumulation of uncharged tRNAThr, which in turn activates Gcn2, leading to phosphorylation of an extra amount of eIF2α. The partial switchover of kinases for eIF2α largely overwhelms the functions of PERK in normal development. Interestingly, although inhibition of Gcn2 and PERK in this stress condition both can reduce the eIF2α phosphorylation levels, their functional consequences in the regulation of target genes and in the rescue of the angiogenic phenotypes are dramatically different. Indeed, genetic and pharmacological manipulations of these pathways validate that the Gcn2-mediated AAR, but not the Perk-mediated UPR, is required for tars-deficiency induced angiogenesis. Thus, the interconnected AAR and UPR pathways differentially regulate angiogenesis through selective functions and mutual competitions, reflecting the specificity and efficiency of multiple stress response pathways that evolve integrally to enable an organism to sense/respond precisely to various types of stresses.

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