Tumor Virology Research Group, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy.
Cell Death Dis. 2015 Jan 29;6(1):e1625. doi: 10.1038/cddis.2014.572.
Angelman syndrome, a severe neurodevelopmental disease, occurs primarily due to genetic defects, which cause lack of expression or mutations in the wild-type E6AP/UBE3A protein. A proportion of the Angelman syndrome patients bear UBE3A point mutations, which do not interfere with the expression of the full-length protein, however, these individuals still develop physiological conditions of the disease. Interestingly, most of these mutations are catalytically defective, thereby indicating the importance of UBE3A enzymatic activity role in the Angelman syndrome pathology. In this study, we show that Angelman syndrome-associated mutants interact strongly with the proteasome via the S5a proteasomal subunit, resulting in an overall inhibitory effect on the proteolytic activity of the proteasome. Our results suggest that mutated catalytically inactive forms of UBE3A may cause defects in overall proteasome function, which could have an important role in the Angelman syndrome pathology.
天使综合征是一种严重的神经发育疾病，主要由基因缺陷引起，导致野生型 E6AP/UBE3A 蛋白表达缺失或突变。一部分天使综合征患者存在 UBE3A 点突变，这些突变并不影响全长蛋白的表达，但这些个体仍会出现疾病的生理状况。有趣的是，这些突变大多数是催化缺陷型的，这表明 UBE3A 酶活性在天使综合征发病机制中的重要性。在这项研究中，我们发现天使综合征相关突变体通过 S5a 蛋白酶体亚基与蛋白酶体强烈相互作用，导致蛋白酶体的整体蛋白水解活性受到抑制。我们的结果表明，突变的催化失活形式的 UBE3A 可能导致蛋白酶体整体功能缺陷，这可能在天使综合征发病机制中发挥重要作用。
