UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development

Yafei Cai, Wenhu Pi, Satish Sivaprakasam, Xiaobin Zhu, Mingsheng Zhang, Jijun Chen, Levi H Makala, Chunwan Lu, Jianchu Wu, Yong Teng, Betty Sue Pace, Dorothy Tuan Lo, Nagendra Singh, Honglin Li

Research output: Contribution to journalArticle

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Abstract

The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined. In this study, we report that UFBP1 is indispensable for embryonic development and hematopoiesis. While germ-line deletion of UFBP1 caused defective erythroid development and embryonic lethality, somatic ablation of UFBP1 impaired adult hematopoiesis, resulting in pancytopenia and animal death. At the cellular level, UFBP1 deficiency led to elevated ER (endoplasmic reticulum) stress and activation of unfolded protein response (UPR), and consequently cell death of hematopoietic stem/progenitor cells. In addition, loss of UFBP1 suppressed expression of erythroid transcription factors GATA-1 and KLF1 and blocked erythroid differentiation from CFU-Es (colony forming unit-erythroid) to proerythroblasts. Interestingly, depletion of Uba5, a Ufm1 E1 enzyme, also caused elevation of ER stress and under-expression of erythroid transcription factors in erythroleukemia K562 cells. By contrast, knockdown of ASC1, a newly identified Ufm1 target that functions as a transcriptional co-activator of hormone receptors, led to down-regulation of erythroid transcription factors, but did not elevate basal ER stress. Furthermore, we found that ASC1 was associated with the promoters of GATA-1 and Klf1 in a UFBP1-dependent manner. Taken together, our findings suggest that UFBP1, along with ASC1 and other ufmylation components, play pleiotropic roles in regulation of hematopoietic cell survival and differentiation via modulating ER homeostasis and erythroid lineage-specific gene expression. Modulating the activity of this novel ubiquitin-like system may represent a novel approach to treat blood-related diseases such as anemia.

Original languageEnglish (US)
Article numbere1005643
JournalPLoS Genetics
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2015

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Endoplasmic Reticulum Stress
endoplasmic reticulum
Embryonic Development
Hematopoiesis
Hematopoietic Stem Cells
Ubiquitin
hematopoiesis
GATA1 Transcription Factor
Transcription Factors
ubiquitin
Unfolded Protein Response
stem cells
Erythroblasts
Leukemia, Erythroblastic, Acute
Erythroid Precursor Cells
Pancytopenia
protein
Ubiquitin-Protein Ligases
anemia
embryogenesis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. / Cai, Yafei; Pi, Wenhu; Sivaprakasam, Satish; Zhu, Xiaobin; Zhang, Mingsheng; Chen, Jijun; Makala, Levi H; Lu, Chunwan; Wu, Jianchu; Teng, Yong; Pace, Betty Sue; Tuan Lo, Dorothy; Singh, Nagendra; Li, Honglin.

In: PLoS Genetics, Vol. 11, No. 11, e1005643, 01.11.2015.

Research output: Contribution to journalArticle

Cai, Yafei ; Pi, Wenhu ; Sivaprakasam, Satish ; Zhu, Xiaobin ; Zhang, Mingsheng ; Chen, Jijun ; Makala, Levi H ; Lu, Chunwan ; Wu, Jianchu ; Teng, Yong ; Pace, Betty Sue ; Tuan Lo, Dorothy ; Singh, Nagendra ; Li, Honglin. / UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. In: PLoS Genetics. 2015 ; Vol. 11, No. 11.
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abstract = "The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined. In this study, we report that UFBP1 is indispensable for embryonic development and hematopoiesis. While germ-line deletion of UFBP1 caused defective erythroid development and embryonic lethality, somatic ablation of UFBP1 impaired adult hematopoiesis, resulting in pancytopenia and animal death. At the cellular level, UFBP1 deficiency led to elevated ER (endoplasmic reticulum) stress and activation of unfolded protein response (UPR), and consequently cell death of hematopoietic stem/progenitor cells. In addition, loss of UFBP1 suppressed expression of erythroid transcription factors GATA-1 and KLF1 and blocked erythroid differentiation from CFU-Es (colony forming unit-erythroid) to proerythroblasts. Interestingly, depletion of Uba5, a Ufm1 E1 enzyme, also caused elevation of ER stress and under-expression of erythroid transcription factors in erythroleukemia K562 cells. By contrast, knockdown of ASC1, a newly identified Ufm1 target that functions as a transcriptional co-activator of hormone receptors, led to down-regulation of erythroid transcription factors, but did not elevate basal ER stress. Furthermore, we found that ASC1 was associated with the promoters of GATA-1 and Klf1 in a UFBP1-dependent manner. Taken together, our findings suggest that UFBP1, along with ASC1 and other ufmylation components, play pleiotropic roles in regulation of hematopoietic cell survival and differentiation via modulating ER homeostasis and erythroid lineage-specific gene expression. Modulating the activity of this novel ubiquitin-like system may represent a novel approach to treat blood-related diseases such as anemia.",
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AU - Zhang, Mingsheng

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