SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination

• Type of Material: Article
• Authors: Hong-Bin Luo, Huazhong University of Science & Technology; Yiyuan Xia, Emory University; Xi-Ji Shu, Jianghan University; Zan-Chao Liu, Huazhong University of Science & Technology; Ye Feng, Huazhong University of Science & Technology; Xing-Hua Liu, Huazhong University of Science & Technology; Guang Yu, Huazhong University of Science & Technology; Gang Yin, Huazhong University of Science & Technology; Yan-Si Xiong, Huazhong University of Science & Technology; Kuan Zeng, Huazhong University of Science & Technology; Jun Jiang, Huazhong University of Science & Technology; Keqiang Ye, Emory University; Xiao-Chuan Wang, Huazhong University of Science & Technology; Jian-Zhi Wang, Huazhong University of Science & Technology
• Language: English
• Date: 2014-11-18
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: NATIONAL ACADEMY OF SCIENCES
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1417548111
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 111
• Issue: 46
• Start Page: 16586
• End Page: 16591
• Grant/Funding Information: This work was supported in part by Grants 81271405 and 91132305 from the National Natural Science Foundation of China, and Grant 2013DFG32670 from Ministry of Science and Technology of the People's Republic of China.
• Keywords: ALZHEIMER NEUROFIBRILLARY DEGENERATION; Science & Technology - Other Topics; phosphorylation; AGGREGATION; Science & Technology; ubiquitination; tau; SUMO-1 MODIFICATION; GLYCOGEN-SYNTHASE KINASE-3; DISEASE; degradation; Multidisciplinary Sciences; HYPERPHOSPHORYLATED-TAU; PAIRED HELICAL FILAMENTS; SUMOylation; PHOSPHATASE 2A; PROTEIN-TAU; ABNORMAL PHOSPHORYLATION
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

Abstract

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 β-amyloid exposure of rat primary hippocampal neurons induces a dosedependent 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.