Modification of ASC1 by UFM1 Is Crucial for ERα Transactivation and Breast Cancer Development

Yoo, Hee Min; Kang, Sung Hwan; Kim, Jae Yeon; Lee, Joo Eun; Seong, Min Woo; Lee, Seong Won; Ka, Seung Hyeun; Sou, Yu‐shin; Komatsu, Masaaki; Tanaka, Keiji; Lee, Sang Kun; Noh, Dong Young; Baek, Sung Hee; Jeon, Young Joo; Chung, Chin Ha

doi:10.1016/j.molcel.2014.08.007

Cited by 176 publications

(284 citation statements)

References 43 publications

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“…Recent studies have demonstrated that RCAD functions as a Ufm1 E3 ligase to promote ufmylation of DDRGK1 and ASC1. 3,12 Interestingly, Uba5 and RCAD KO mice exhibit broad phenotypic similarities. First, inactivation of either gene led to defective embryonic erythropoiesis and lethality ( Figure 1 and Tatsumi et al…”

Section: Discussionmentioning

confidence: 99%

“…In line with its role in ufmylation, knockdown of endogenous RCAD resulted in attenuated ufmylation of endogenous Ufm1 targets. 7,8 More recently, Yoo et al 12 found that Ufl1-mediated ufmylation of ASC1, a nuclear receptor co-activator, played a crucial role in estrogen receptor signaling and breast cancer development. Nonetheless, the in vivo function of RCAD remains completely unknown.…”

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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: Discussionmentioning

confidence: 99%

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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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“…6 is a ubiquitin (Ub)-like protein (UBL) that shares structural, but little sequence, similarity with Ub and, like Ub, can be conjugated to lysine residues of itself or target proteins (1)(2)(3). UFM1 is activated by the E1 enzyme UBA5, which forms a high-energy thioester bond between its catalytic cysteine and the exposed C-terminal glycine of UFM1.…”

Section: Ufm1mentioning

confidence: 99%

“…For example, by covalently modifying the transcriptional co-activator ASC1, polyUFM1 chains enhance the association of ASC1 with p300 and SRC1 (steroid receptor coactivator 1), leading to the transcriptional activation of estrogen receptor ␣ target genes and improved anchorage-independent growth of tumor cells (3). The role of UFBP1 (UFM1-binding protein 1 containing a PCI domain, also known as C20orf116 and DDRGK1) modification by UFM1 is less clear.…”

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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“…Intriguingly, Homrich et al observed that the overexpression of UFM1 markedly increased neural cell adhesion molecule (NCAM) endocytosis , indicating that NCAM ufmylation affects its trafficking 18) . Most recently, Yoo et al 19) demonstrated that activating signal cointegrator 1 (ASC1) is a novel target for ufmylation and ufmylation of ASC1 and plays a crucial role in the development of estrogen receptor-apositive breast cancer. These data indicate diverse functions of UFM1 depending on the function of the target protein.…”

Section: Introductionmentioning

confidence: 99%

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

J Atheroscler Thromb

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Aim: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Methods: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE / mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. Results: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor (LXR ) activation, which was confirmed by the observation that LXR siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Conclusions: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXR -dependent pathway.

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Modification of ASC1 by UFM1 Is Crucial for ERα Transactivation and Breast Cancer Development

Cited by 176 publications

References 43 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

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

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