Novel insights into the role of UBE3A in apoptosis and mitochondrial function

UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression leads to Angelman syndrome (AS), while its overexpression is associated with autism. In spite of extensive research, our understanding of UBE3A roles is still limited. We investigated the cellular and molecular effects of Ube3a deletion in mouse embryonic fibroblasts (MEFs) and Angelman syndrome (AS) mouse model hippocampi. Cell cultures of MEFs exhibited enhanced proliferation together with reduced apoptosis when Ube3a was deleted. These findings were supported by transcriptome and proteome analyses. Furthermore, transcriptome analyses revealed alterations in mitochondria-related genes. This finding emphasizes the critical role of mitochondria in governing the balance between proliferation and apoptosis, which is essential for normal brain development.

UBE3A基因编码一种具备两种已知功能的蛋白质：其一为泛素E3连接酶（ubiquitin E3-ligase），可催化泛素与底物蛋白结合；其二为类固醇激素受体辅激活因子。UBE3A最为人熟知的是其在神经元功能中的关键作用。UBE3A蛋白表达缺失会引发天使综合征（Angelman syndrome, AS），而其过表达则与自闭症发病相关。尽管已有广泛研究，我们对UBE3A的功能作用仍了解有限。本研究探究了Ube3a基因敲除在小鼠胚胎成纤维细胞（mouse embryonic fibroblasts, MEFs）以及天使综合征模型小鼠海马体中的细胞与分子效应。结果显示，Ube3a敲除的MEF细胞培养物增殖能力增强，同时细胞凋亡水平降低，该发现得到了转录组与蛋白质组分析的验证。此外，转录组分析还揭示了线粒体相关基因的表达异常。这一发现突显了线粒体在调控细胞增殖与凋亡平衡中的核心作用，而该平衡对于正常大脑发育至关重要。