α1-syntrophin modulates turnover of ABCA1
α1-syntrophin modulates turnover of ABCA1
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DOI：
10.1074/jbc.m313436200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Ueda, K
中科院分区：
文献类型：
--
作者：
Munehira, Y;Ohnishi, T;Ueda, K
ABCA 1（ATP结合盒转运蛋白A1）介导细胞胆固醇和磷脂的释放以形成高密度脂蛋白。ABCA 1的功能在转录和转录后水平受到高度调节，合成的ABCA 1蛋白质迅速翻转，半衰期为1 - 2 h。为了检测ABCA 1的功能是否受相关蛋白的调节，用ABCA 1的C-末端120个氨基酸筛选酵母双杂交文库。发现两种PDZ（PSD 95-Discs large-ZO 1）蛋白，alpha 1-syntrophin和Lin 7与ABCA 1相互作用。免疫沉淀显示，α 1-syntrophin与ABCA 1强烈的相互作用，这种相互作用是通过ABCA 1的C-末端三个氨基酸SYV。在人胚肾293细胞中共表达α 1-促突触蛋白延缓了ABCA 1的降解，使ABCA 1的半衰期比不表达α 1-促突触蛋白的细胞长5倍。这种效应在与ABCA 1相互作用的含PDZ的蛋白质中并不常见，因为也发现与ABCA 1的C末端区域相互作用的Lin 7对ABCA 1的半衰期没有显著影响。α 1-syntrophin的共表达显著增加了apoA-I介导的胆固醇释放。将ABCA 1与小鼠脑中的α 1-促突触素共免疫沉淀。这些结果表明，α 1-syntrophin参与细胞内信号，决定ABCA 1的稳定性和调节细胞胆固醇的释放。
ABCA1 (ATP-binding cassette transporter A1) mediates the release of cellular cholesterol and phospholipid to form high density lipoprotein. Functions of ABCA1 are highly regulated at the transcriptional and post-transcriptional levels, and the synthesized ABCA1 protein turns over rapidly with a half-life of 1 - 2 h. To examine whether the functions of ABCA1 are modulated by associated proteins, a yeast two-hybrid library was screened with the C-terminal 120 amino acids of ABCA1. Two PDZ (PSD95-Discs large-ZO1) proteins, alpha1-syntrophin and Lin7, were found to interact with ABCA1. Immunoprecipitation revealed that alpha1-syntrophin interacted with ABCA1 strongly and that the interaction was via the C-terminal three amino acids SYV of ABCA1. Co-expression of alpha1-syntrophin in human embryonic kidney 293 cells retarded degradation of ABCA1 and made the half-life of ABCA1 five times longer than in the cells not expressing alpha1-syntrophin. This effect is not common among PDZ-containing proteins interacting with ABCA1, because Lin7, which was also found to interact with the C terminus region of ABCA1, did not have a significant effect on the half-life of ABCA1. Co-expression of alpha1-syntrophin significantly increased the apoA-I-mediated release of cholesterol. ABCA1 was co-immunoprecipitated with alpha1-syntrophin from mouse brain. These results suggest that alpha1-syntrophin is involved in intracellular signaling, which determines the stability of ABCA1 and modulates cellular cholesterol release.