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标题：SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination
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作者：Hong-Bin Luo ; Yi-Yuan Xia ; Xi-Ji Shu 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16586-16591
DOI：10.1073/pnas.1417548111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIntracellular accumulation of the abnormally modified tau is hallmark pathology of AD, but the mechanism leading to tau aggregation is not fully characterized. In the present study, we studied the effects of tau SUMOylation on its phosphorylation, ubiquitination, degradation, and aggregation. We discovered that sumoylation competes with ubiquitination in modifying tau, correlating with tau hyperphosphorylation. Identification of the posttranslational modification on tau provides the new insight into the molecular mechanism in tau aggregation. Intracellular accumulation of the abnormally modified tau is hallmark pathology of Alzheimer's disease (AD), but the mechanism leading to tau aggregation is not fully characterized. Here, we studied the effects of tau SUMOylation on its phosphorylation, ubiquitination, and degradation. We show that tau SUMOylation induces tau hyperphosphorylation at multiple AD-associated sites, whereas site-specific mutagenesis of tau at K340R (the SUMOylation site) or simultaneous inhibition of tau SUMOylation by ginkgolic acid abolishes the effect of small ubiquitin-like modifier protein 1 (SUMO-1). Conversely, tau hyperphosphorylation promotes its SUMOylation; the latter in turn inhibits tau degradation with reduction of solubility and ubiquitination of tau proteins. Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and {beta}-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.
关键词：SUMOylation ; tau ; phosphorylation ; ubiquitination ; degradation