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
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DOI：
10.1038/cdd.2015.51
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发表时间：
2015-12-01
影响因子：
12.4
通讯作者：
Li, H.
中科院分区：
文献类型：
--
作者：
Zhang, M.;Zhu, X.;Li, H.
Ufm 1偶联系统是一种新型的泛素样修饰系统，由Ufm 1、Uba 5（E1）、Ufc 1（E2）和E3连接酶组成。据报道，RCAD/Ufl 1（也称为KIAA 0776、NLBP和Maxer）在DDRGK 1和ASC 1蛋白的ufmylation（Ufm 1介导的缀合）中起Ufm 1 E3连接酶的作用。它还涉及雌激素受体信号传导，未折叠蛋白反应（UPR）和神经变性，但其生理功能仍然完全未知。在这项研究中，我们报告RCAD/Ufl 1是胚胎发育，造血干细胞（HSC）的生存和红系分化所必需的。RCAD/Ufl 1的生殖系和体细胞缺失均损害造血发育，导致严重贫血、血细胞减少和最终动物死亡。耗尽RCAD/Ufl 1引起内质网应激升高，并诱发骨髓细胞中的UPR。此外，RCAD/Ufl 1的缺失阻断了HSC的自噬降解，增加了线粒体质量和活性氧，并导致DNA损伤反应、p53激活和增强的细胞死亡。总的来说，我们的研究为RCAD/Ufl 1在小鼠造血和发育中不可或缺的作用提供了第一个遗传证据。RCAD/Ufl 1作为细胞应激反应的关键调节因子的发现揭示了包括RCAD/Ufl 1及其相关蛋白在内的新型蛋白质网络在调节细胞稳态中的作用。
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.