SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination.
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 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.
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Hong-Bin
HB
Luo
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Yi-Yuan
YY
Xia
Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China;
Xi-Ji
XJ
Shu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Zan-Chao
ZC
Liu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Ye
Y
Feng
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Xing-Hua
XH
Liu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Guang
G
Yu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Gang
G
Yin
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Yan-Si
YS
Xiong
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Kuan
K
Zeng
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
Jun
J
Jiang
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; and.
Keqiang
K
Ye
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Division of Neurodegenerative Disorders, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China wxch@mails.tjmu.edu.cn wangjz@mails.tjmu.edu.cn.
Xiao-Chuan
XC
Wang
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Division of Neurodegenerative Disorders, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China wxch@mails.tjmu.edu.cn wangjz@mails.tjmu.edu.cn.
Jian-Zhi
JZ
Wang
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D012995:Solubility; D058207:Sumoylation; D054875:Ubiquitination; D000077191:Wortmannin; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000730:Androstadienes; D007211:Indoles; C054369:MAPT protein, human; D008301:Maleimides; C489131:Mapt protein, rat; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D012459:Salicylates; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; C112485:ginkgolic acid; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; C070515:bisindolylmaleimide I; D000077191:Wortmannin
SUMOylation; degradation; phosphorylation; tau; ubiquitination