Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway

Fanghui Chen, Chaofeng Xing, Wei Zhang, Jun Li, Tianxiang Hu, Lian Li, Honglin Li, Yafei Cai

Research output: Contribution to journalArticle

Abstract

Ufmylation was proved to play a crucial role in hematopoietic stem cell (HSC) survival and erythroid differentiation, ufmylation deficiency induces acute anemia and lethality of embryos and adults in mouse models. To screen some compounds to rescue phenotypes induced by gene deletion, in this study, we used DDRGK1F/F; CreERT2 conditional knockout mice, DDRGK1F/F; CreERT2 bone marrow (BM) and fetal liver cells (FL), Uba5, and DDRGK1 knockdown human CD34 cell in vivo and in vitro, we found salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promoted erythropoiesis at early stage, and partly rescued the acute anemia induce by DDRGK1 deficiency through upregulation of ufmylation and erythroid transcription factors. In phenylhydrazine (PHZ)-induced hemolytic anemia mice, interestingly, salubrinal could significantly improve hemocrit and red blood cell (RBC) indices of the mice treated with PHZ via upregulation of ufmylation. Its novel function was verified to attenuate unfolded protein response (UPR) and cell death programs, and to keep endoplasmic reticulum (ER) homeostasis in HSCs. Taken together results, it suggested that salubrinal may be a promising antianemic agent targeted by ufmylation.

Original languageEnglish (US)
Pages (from-to)18560-18570
Number of pages11
JournalJournal of Cellular Physiology
Volume234
Issue number10
DOIs
Publication statusPublished - Oct 2019

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Keywords

  • DDRGK1
  • erythropoiesis
  • salubrinal
  • ufmylation

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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