The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice

Tatsumi, Kanako; Yamamoto-Mukai, Harumi; Shimizu, Ritsuko; Waguri, Satoshi; Sou, Yu‐shin; Sakamoto, Ayako; Taya, Choji; Shitara, Hiroshi; Hara, Takahiko; Chung, Chin Ha; Tanaka, Keiji; Yamamoto, Masayuki; Komatsu, Masaaki

doi:10.1038/ncomms1182

Cited by 132 publications

(162 citation statements)

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“…Additionally, there were a high number of abnormal multinucleated erythrocytes in RCAD −/− embryos (Figures 1e-g), a phenotype reminiscent of Uba5 null embryos. 2 The numbers of erythroid colony-forming units (CFU-Es) and more immature erythroid burst-forming units (BFU-Es) from fetal livers (E11.5) were significantly lower in RCAD −/− fetal livers (Figure 1h), suggesting impaired development of erythroid progenitors. Accordingly, the genes associated with the erythroid lineage, including ε-globin, βH1-globin and transcription factors GATA-1/FOG-1 and Klf1, were markedly underexpressed in RCAD −/− fetal livers (Figure 1i).…”

Section: Rcad Is Essential For Embryonic Erythroid Developmentmentioning

confidence: 99%

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RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

et al. 2015

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The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis. Cell Death and Differentiation (2015) 22, 1922-1934 doi:10.1038/cdd.2015 .51; published online 8 May 2015The Ufm1 (Ubiquitin-fold modifier 1) conjugation system is a novel ubiquitin-like (Ubl) modification system that shares biochemical features with other Ubl systems.1 Ufm1 modifies its target proteins through a biochemical pathway catalyzed by specific E1 (Uba5), E2 (Ufc1) and E3 enzyme(s) even though the identities of E3 ligases remain mostly elusive. Genetic study from Uba5 knockout (KO) mice has shown that Uba5 is indispensable for embryonic erythropoiesis, highlighting the pivotal role of this novel Ubl system in animal development. 2Yet its role in adult erythropoiesis and other developmental processes is largely unexplored and the underlying molecular mechanism remains poorly understood.Regulator of C53 and DDRGK1 (also known as KIAA0776, Ufl1, NLBP and Maxer, referred to as RCAD hereafter) has recently been identified by independent studies as an important regulator of several signaling pathways, including protein ufmylation, NF-κB signaling and unfolded protein response (UPR).3-9 Endogenous RCAD forms a complex with two proteins: C53 (also known as LZAP and Cdk5rap3) 5,6,10 and DDRGK1 (also designated as C20orf116, Dashurin and UFBP1), 3,6,7,11 and regulates the stability of its binding partners. 5,6 Intriguingly, Tatsumi et al. 3 found that Ufl1 (same as RCAD) promoted ufmylation of DDRGK1, suggesting that RCAD may function as an E3 ligase for ufmylation of DDRGK1. In line with its role in ufmylation, knockdown of endogenous RCAD resulted in attenuated ufmylation of endogen...

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Section: Rcad Is Essential For Embryonic Erythroid Developmentmentioning

confidence: 99%

“…Genetic study from Uba5 knockout (KO) mice has shown that Uba5 is indispensable for embryonic erythropoiesis, highlighting the pivotal role of this novel Ubl system in animal development. 2 Yet its role in adult erythropoiesis and other developmental processes is largely unexplored and the underlying molecular mechanism remains poorly understood.…”

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confidence: 99%

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

et al. 2015

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“…Interestingly, conditions that induce ER stress lead to increased expression of components of the UFM1 conjugation system, whereas their downregulation exacerbates ER stress and sensitizes cells to apoptosis (5)(6)(7)(8)(9). Of note, the ufmylation pathway is indispensable for erythro-and megakaryopoiesis, with Uba5 Ϫ/Ϫ , Ufl1 Ϫ/Ϫ , and Ufbp1 Ϫ/Ϫ mice dying in utero because of severe anemia connected to the reduced numbers of functionally differentiated erythrocytes (5,8,10).…”

Section: Ufm1mentioning

confidence: 99%

Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation

Habisov

Huber

Ichimura

et al. 2016

Journal of Biological Chemistry

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The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifierconjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/␥-aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub)-like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway.

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“…This region is referred to as the Gata1 hematopoietic regulatory domain (G1HRD; Fig. 1b) and utilized as an extremely useful genetic tool that directs erythroid-and megakaryocyte-specific expression of various transgenes [21][22][23].…”

Section: Gata1 Gene Structure and Gata1 Hematopoietic Regulatory Domainmentioning

confidence: 99%

A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation

Moriguchi

Yamamoto

2014

Int J Hematol

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GATA transcription factor family members GATA1 and GATA2 play crucial roles in the regulation of lineage-restricted genes during erythroid differentiation. GATA1 is indispensable for survival and terminal differentiation of erythroid, megakaryocytic and eosinophilic progenitors, whereas GATA2 regulates proliferation and maintenance of hematopoietic stem and progenitor cells. Expression levels of GATA1 and GATA2 are primarily regulated at the transcriptional level through auto-and reciprocal regulatory networks formed by these GATA factors. The dynamic and strictly controlled change of expression from GATA2 to GATA1 during erythropoiesis has been referred to as GATA factor switching, which plays a crucial role in erythropoiesis. The regulatory network comprising GATA1 and GATA2 gives rise to the stage-specific changes in Gata1 and Gata2 gene expression during erythroid differentiation, which ensures specific expression of early and late erythroid genes at each stage. Recent studies have also shed light on the genome-wide binding profiles of GATA1 and GATA2, and the significance of epigenetic modification of Gata1 gene during erythroid differentiation. This review summarizes the current understanding of network regulation underlying stagedependent Gata1 and Gata2 gene expressions and the functional contribution of these GATA factors in erythroid differentiation.

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The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice

Cited by 132 publications

References 28 publications

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation

A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation

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