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
StatePublished - Oct 1 2019

Fingerprint

Erythropoiesis
Anemia
Up-Regulation
Unfolded Protein Response
Erythrocyte Indices
Hemolytic Anemia
Gene Deletion
Cell death
Hematopoietic Stem Cells
Stem cells
Knockout Mice
Endoplasmic Reticulum
Liver
Cell Survival
Bone
Homeostasis
Blood
Cell Death
Transcription Factors
Embryonic Structures

Keywords

  • DDRGK1
  • erythropoiesis
  • salubrinal
  • ufmylation

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway. / Chen, Fanghui; Xing, Chaofeng; Zhang, Wei; Li, Jun; Hu, Tianxiang; Li, Lian; Li, Honglin; Cai, Yafei.

In: Journal of Cellular Physiology, Vol. 234, No. 10, 01.10.2019, p. 18560-18570.

Research output: Contribution to journalArticle

Chen, Fanghui ; Xing, Chaofeng ; Zhang, Wei ; Li, Jun ; Hu, Tianxiang ; Li, Lian ; Li, Honglin ; Cai, Yafei. / Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway. In: Journal of Cellular Physiology. 2019 ; Vol. 234, No. 10. pp. 18560-18570.
@article{5999d3dd1db046f39962ac9a3d2663b3,
title = "Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway",
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.",
keywords = "DDRGK1, erythropoiesis, salubrinal, ufmylation",
author = "Fanghui Chen and Chaofeng Xing and Wei Zhang and Jun Li and Tianxiang Hu and Lian Li and Honglin Li and Yafei Cai",
year = "2019",
month = "10",
day = "1",
doi = "10.1002/jcp.28493",
language = "English (US)",
volume = "234",
pages = "18560--18570",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Salubrinal, a novel inhibitor of eIF-2α dephosphorylation, promotes erythropoiesis at early stage targeted by ufmylation pathway

AU - Chen, Fanghui

AU - Xing, Chaofeng

AU - Zhang, Wei

AU - Li, Jun

AU - Hu, Tianxiang

AU - Li, Lian

AU - Li, Honglin

AU - Cai, Yafei

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - DDRGK1

KW - erythropoiesis

KW - salubrinal

KW - ufmylation

UR - http://www.scopus.com/inward/record.url?scp=85063376657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063376657&partnerID=8YFLogxK

U2 - 10.1002/jcp.28493

DO - 10.1002/jcp.28493

M3 - Article

VL - 234

SP - 18560

EP - 18570

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 10

ER -