Song Sungmin, Kim So-Young, Hong Yeon-Mi, Jo Dong-Gyu, Lee Joo-Yong, Shim Sang Mi, Chung Chul-Woong, Seo Soo Jung, Yoo Yung Joon, Koh Jae-Young, Lee Min Chul, Yates Allan J, Ichijo Hidenori, Jung Yong-Keun
Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, South Korea.
Mol Cell. 2003 Sep;12(3):553-63. doi: 10.1016/j.molcel.2003.08.005.
The ubiquitin/proteasome system has been proposed to play an important role in Alzheimer's disease (AD) pathogenesis. However, the critical factor(s) modulating both amyloid-beta peptide (Abeta) neurotoxicity and ubiquitin/proteasome system in AD are not known. We report the isolation of an unusual ubiquitin-conjugating enzyme, E2-25K/Hip-2, as a mediator of Abeta toxicity. The expression of E2-25K/Hip-2 was upregulated in the neurons exposed to Abeta(1-42) in vivo and in culture. Enzymatic activity of E2-25K/Hip-2 was required for both Abeta(1-42) neurotoxicity and inhibition of proteasome activity. E2-25K/Hip-2 functioned upstream of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK) in Abeta(1-42) toxicity. Further, the ubiquitin mutant, UBB+1, a potent inhibitor of the proteasome which is found in Alzheimer's brains, was colocalized and functionally interacted with E2-25K/Hip-2 in mediating neurotoxicity. These results suggest that E2-25K/Hip-2 is a crucial factor in regulating Abeta neurotoxicity and could play a role in the pathogenesis of Alzheimer's disease.
泛素/蛋白酶体系统被认为在阿尔茨海默病（AD）的发病机制中起重要作用。然而，在AD中调节淀粉样β肽（Aβ）神经毒性和泛素/蛋白酶体系统的关键因素尚不清楚。我们报告分离出一种不寻常的泛素结合酶E2-25K/Hip-2，作为Aβ毒性的介质。E2-25K/Hip-2的表达在体内和体外暴露于Aβ（1-42）的神经元中上调。Aβ（1-42）神经毒性和蛋白酶体活性抑制都需要E2-25K/Hip-2的酶活性。在Aβ（1-42）毒性中，E2-25K/Hip-2在凋亡信号调节激酶1（ASK1）和c-Jun氨基末端激酶（JNK）的上游发挥作用。此外，泛素突变体UBB+1是一种在阿尔茨海默病大脑中发现的蛋白酶体强效抑制剂，在介导神经毒性方面与E2-25K/Hip-2共定位并在功能上相互作用。这些结果表明，E2-25K/Hip-2是调节Aβ神经毒性的关键因素，可能在阿尔茨海默病的发病机制中起作用。
