Proceedings of the National Academy of Sciences - PNAS, 2014-11, Vol.111 (46), p.16586-16591
2014
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- Autor(en) / Beteiligte
- Titel
- SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2014-11, Vol.111 (46), p.16586-16591
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Significance Intracellular 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 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1417548111Titel-ID: cdi_proquest_journals_1627727457
- Format
- –
- Schlagworte
- Aggregation, Alzheimer Disease - metabolism, Alzheimer Disease - pathology, Alzheimer's disease, Alzheimers disease, Amino Acid Substitution, Amyloid beta-Peptides - pharmacology, Androstadienes - pharmacology, Animals, Antibodies, Biological Sciences, Brain, Cerebral Cortex - metabolism, Cerebral Cortex - pathology, Female, Glycogen Synthase Kinase 3 - metabolism, Glycogen Synthase Kinase 3 beta, HEK293 Cells, Hippocampus - metabolism, Humans, Indoles - pharmacology, Male, Maleimides - pharmacology, Microtubules, Middle Aged, Mutagenesis, Mutagenesis, Site-Directed, Mutation, Missense, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Neurons, Peptide Fragments - pharmacology, Phosphorylation, Point Mutation, Proteasome Endopeptidase Complex - metabolism, Protein Processing, Post-Translational, Proteins, Proteolysis, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins - metabolism, Salicylates - pharmacology, Solubility, SUMO-1 Protein - genetics, SUMO-1 Protein - metabolism, Sumoylation, Tau proteins, tau Proteins - genetics, tau Proteins - metabolism, Ubiquitination, Ubiquitins, Western blotting