Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation.
Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation.
复制标题
泛素蛋白的鉴定，这是一种新型的presenilin相互作用者，可增加Presenilin蛋白的积累。
DOI：
10.1083/jcb.151.4.847
复制
发表时间：
2000-11-13
影响因子：
7.8
通讯作者：
Monteiro, M J
中科院分区：
文献类型：
--
作者：
Mah, A L;Perry, G;Smith, M A;Monteiro, M J
编码早老素-1和早老素-2（PS1和PS2）的高度同源早老素基因中的突变与早发性阿尔茨海默病（AD）相关。然而，除了在早期发育中的作用外，无论是早老素的正常功能还是突变蛋白引起AD的机制都没有很好的理解。在这里，我们描述了一种新的人类相互作用的早老蛋白命名为ubiquilin的属性。酵母双杂交（Y2 H）的相互作用，谷胱甘肽S-转移酶下拉实验，并在体内表达的蛋白质的共定位，与coimmunoprecipitation和细胞分级分离的研究，提供了令人信服的证据，泛素与PS1和PS2相互作用。泛素是值得注意的，因为它含有多个泛素相关的结构域，通常被认为涉及靶向蛋白质降解。然而，我们发现泛素促进早老素蛋白的积累。脉冲标记实验表明，ubiquilin促进增加早老素的合成，而基本上不改变早老素蛋白的半衰期。免疫组织化学的人脑组织与泛蛋白特异性抗体显示显着染色的神经元。此外，抗泛素抗体分别对AD和帕金森病患者大脑中的神经元缠结和路易体进行了强有力的染色。我们的研究结果表明，ubiquilin可能是一个重要的调制器的早老素蛋白的积累和ubiquilin蛋白与神经病理神经元缠结和路易体夹杂物在患病的大脑。
Mutations in the highly homologous presenilin genes encoding presenilin-1 and presenilin-2 (PS1 and PS2) are linked to early-onset Alzheimer's disease (AD). However, apart from a role in early development, neither the normal function of the presenilins nor the mechanisms by which mutant proteins cause AD are well understood. We describe here the properties of a novel human interactor of the presenilins named ubiquilin. Yeast two-hybrid (Y2H) interaction, glutathione S-transferase pull-down experiments, and colocalization of the proteins expressed in vivo, together with coimmunoprecipitation and cell fractionation studies, provide compelling evidence that ubiquilin interacts with both PS1 and PS2. Ubiquilin is noteworthy since it contains multiple ubiquitin-related domains typically thought to be involved in targeting proteins for degradation. However, we show that ubiquilin promotes presenilin protein accumulation. Pulse-labeling experiments indicate that ubiquilin facilitates increased presenilin synthesis without substantially changing presenilin protein half-life. Immunohistochemistry of human brain tissue with ubiquilin-specific antibodies revealed prominent staining of neurons. Moreover, the anti-ubiquilin antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD and Parkinson's disease affected brains, respectively. Our results indicate that ubiquilin may be an important modulator of presenilin protein accumulation and that ubiquilin protein is associated with neuropathological neurofibrillary tangles and Lewy body inclusions in diseased brain.