Deficiency of Murine UFM1-Specific E3 Ligase Causes Microcephaly and Inflammation
Deficiency of Murine UFM1-Specific E3 Ligase Causes Microcephaly and Inflammation
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DOI：
10.1007/s12035-022-02979-0
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发表时间：
2022-08-06
影响因子：
5.1
通讯作者：
Li, Honglin
中科院分区：
文献类型：
--
作者：
Zhang, Jie;Zhu, Huabin;Li, Honglin
UFM1偶联系统是一种泛素（Ub）样修饰系统，对动物发育和多组织器官的正常生理至关重要。它由UFM1（一种ub样修饰剂）和UFM1特异性酶（即El酶UBA5、E2酶UFC1 E2和E3连接酶）组成，这些酶催化UFM1与其特异性蛋白靶标结合。临床研究发现，人类UFM1、UBA5和UFC1基因中罕见的遗传变异与早发性脑病和脑发育缺陷有关，强烈提示UFM1系统在神经系统中的关键作用。然而，该系统在成人脑中的生理功能尚未明确。在本研究中，我们研究了UFM1 E3连接酶在成年小鼠中的作用，发现UFM1 E3连接酶的两个组成部分UFL1和UFBP1蛋白都是成年小鼠成熟神经元存活所必需的。神经元特异性缺失UFL1或UFBP1均可导致显著的神经元丢失和炎症反应升高。有趣的是，丢失UFBP1基因的一个等位基因会导致癫痫样事件的发生。我们的研究为UFM1 E3连接酶在成熟神经元中不可或缺的作用提供了遗传学证据，进一步证明了UFM1系统在神经系统中的重要性。
The UFM1 conjugation system is a Ubiquitin (Ub)-like modification system that is essential for animal development and normal physiology of multiple tissues and organs. It consists of UFM1, a Ub-like modifier, and the UFM1-specific enzymes (namely El enzyme UBA5, E2 enzyme UFC1 E2, and E3 ligases) that catalyze conjugation of UFM1 to its specific protein targets. Clinical studies have identified rare genetic variants in human UFM1, UBA5 and UFC1 genes that were linked to early-onset encephalopathy and defective brain development, strongly suggesting the critical role of the UFM1 system in the nervous system. Yet, the physiological function of this system in adult brain remains not defined. In this study, we investigated the role of UFM1 E3 ligase in adult mouse and found that both UFL1 and UFBP1 proteins, two components of UFM1 E3 ligase, are essential for survival of mature neurons in adult mouse. Neuron-specific deletion of either UFL1 or UFBP1 led to significant neuronal loss and elevation of inflammatory response. Interestingly, loss of one allele of UFBP1 genes caused the occurrence of seizure-like events. Our study has provided genetic evidence for the indispensable role of UFM1 E3 ligase in mature neurons and further demonstrated the importance of the UFM1 system in the nervous system.