Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Kamikitazawa 2-1-6, Setagaya-ku, Tokyo 156-8506, Japan.
Nat Commun. 2011 Feb 8;2:181. doi: 10.1038/ncomms1182.
Post-translational protein modifications are systems designed to expand restricted genomic information through functional conversion of target molecules. Ubiquitin-like post-translational modifiers regulate numerous cellular events through their covalent linkages to target protein(s) by an enzymatic cascade analogous to ubiquitylation consisting of E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development. Mice lacking Uba5 exhibited severe anaemia, followed by death in utero. Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors. Intriguingly, transgenic expression of Uba5 in the erythroid lineage rescued the Uba5-deficient embryos from anaemia and prolonged their survival, demonstrating the importance of Uba5 in cell-autonomous erythroid differentiation. Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.
蛋白质翻译后修饰是通过靶分子的功能转化来扩展有限基因组信息的系统。类泛素化翻译后修饰因子通过类似于泛素化的酶促级联反应与靶蛋白共价连接，从而调节众多细胞事件，该酶促级联反应由E1（激活）、E2（缀合）和E3（连接）酶组成。在本研究中，我们报道了类泛素化修饰因子Ufm1的特异性激活酶Uba5在红细胞生成中的重要作用。缺乏Uba5的小鼠表现出严重贫血，随后在子宫内死亡。虽然Uba5对于促红细胞生成素的产生并非必需，但其基因缺失导致来自常见髓系祖细胞的巨核细胞和红细胞祖细胞发育受损。有趣的是，在红细胞谱系中Uba5的转基因表达使Uba5缺陷型胚胎免于贫血并延长了它们的存活时间，这证明了Uba5在细胞自主红细胞分化中的重要性。我们的结果表明，类泛素化蛋白修饰系统之一，即Ufm1系统，参与了造血作用的调节。
