Mammalian E4 is required for cardiac development and maintenance of the nervous system
Mammalian E4 is required for cardiac development and maintenance of the nervous system
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DOI：
10.1128/mcb.25.24.10953-10964.2005
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发表时间：
2005-12-01
影响因子：
5.3
通讯作者：
Nakayama, KI
中科院分区：
文献类型：
--
作者：
Kaneko-Oshikawa, C;Nakagawa, T;Nakayama, KI
泛素偶联通常需要三种酶：E1， E2和E3。然而，第四种酶（E4）最近被证明是酵母菌中某些类型底物降解所必需的。我们之前在哺乳动物中发现UFD2a（也称为E4B）是E4。在小鼠胚胎发育期间，UFD2a仅在心肌中表达，但在成年小鼠的神经元中大量表达，并与神经退行性疾病的发病机制有关。然而，这种酶的确切生理功能在很大程度上仍然未知。在这里，我们发现缺乏UFD2a的小鼠在子宫内死亡，在发育中的心脏中表现出明显的细胞凋亡。在Ufd2a（-/-）小鼠胚胎成纤维细胞中，E4底物的多泛素化活性大大降低。此外，Ufd2a（+/-）小鼠显示股薄核轴突营养不良，浦肯野细胞变性伴内质网应激。这些动物还患上了神经紊乱。因此，UFD2a似乎对心肌的发育以及保护脊髓小脑神经元免受内质网应激诱导的变性至关重要。
Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a(-/-) mouse embryonic fibroblasts. Furthermore, Ufd2a(+/-) mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.