UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development.
UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development.
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UFBP1 是 Ufm1 缀合系统的关键组成部分，对于 Ufmylation 介导的红细胞发育调节至关重要
DOI：
10.1371/journal.pgen.1005643
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发表时间：
2015-11
期刊：
影响因子：
4.5
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Cai Y;Pi W;Sivaprakasam S;Zhu X;Zhang M;Chen J;Makala L;Lu C;Wu J;Teng Y;Pace B;Tuan D;Singh N;Li H
Ufm1偶联系统是一种泛素样修饰系统，由Ufm1、Uba5 （E1）、Ufc1 （E2）以及定义不明确的E3连接酶和靶标组成。该系统在胚胎发生和红系发育中的重要作用突出了其生物学重要性，但其潜在机制尚不清楚。UFBP1 （Ufm1结合蛋白1，也被称为DDRGK1、Dashurin和C20orf116）是一个假定的Ufm1靶点，但其确切的生理功能及其磷酸化的影响在很大程度上仍不清楚。在这项研究中，我们报道了UFBP1在胚胎发育和造血中是不可或缺的。虽然种系缺失UFBP1会导致红细胞发育缺陷和胚胎死亡，但体细胞消融UFBP1会损害成人造血功能，导致全血细胞减少和动物死亡。在细胞水平上，UFBP1缺乏导致内质网应激升高和未折叠蛋白反应（UPR）的激活，从而导致造血干细胞/祖细胞死亡。此外，UFBP1的缺失抑制了红系转录因子GATA-1和KLF1的表达，并阻止了红系从CFU-Es（集落形成单位-红系）向原红母细胞的分化。有趣的是，Uba5（一种Ufm1 E1酶）的缺失也会导致红白血病K562细胞内质网应激升高和红系转录因子表达不足。相比之下，ASC1（一种新发现的Ufm1靶点，作为激素受体的转录共激活因子）的敲低会导致红系转录因子的下调，但不会升高基础内质网应激。此外，我们发现ASC1以ufbp1依赖的方式与GATA-1和Klf1的启动子相关。综上所述，我们的研究结果表明，UFBP1与ASC1和其他ufmy化成分一起，通过调节内质网稳态和红系特异性基因表达，在造血细胞存活和分化的调节中发挥了多效性作用。调节这种新型泛素样系统的活性可能是治疗贫血等血液相关疾病的一种新方法。
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.