Research Paper|Volume 12, Issue 8|pp 7042—7055

SIRT1 regulates O-GlcNAcylation of tau through OGT

Shu Lu³, Xiaomin Yin^1,², Jia Wang², Qun Gu², Qin Huang², Nana Jin², Dandan Chu², Ziqi Xu¹, Fei Liu^2,⁴, Wei Qian^1,²

¹Department of Biochemistry and Molecular Biology, Medical School, Nantong, Jiangsu, P. R. China
²Jiangsu Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China
³Department of Intensive Care Unit, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P. R. China
⁴Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA

* Equal contribution

Received: October 7, 2019Accepted: March 9, 2020Published: April 20, 2020

Copyright © 2020 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Tau is modified with O-GlcNAcylation extensively in human brain. The O-GlcNAcylation levels of tau are decreased in Alzheimer’s disease (AD) brain. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins including transcriptional factors and associates with neurodegenerative diseases, such as AD. Aberrant SIRT1 expression levels in AD brain is in parallel with the accumulation of tau. cAMP response element binding protein (CREB), a cellular transcription factor, plays a critical role in learning and memory. In this present study, we found SIRT1 deacetylates CREB and inhibits phosphorylation of CREB at Ser133. The inactivated CREB suppresses OGT expression and therefore decreases the O-GlcNAcylation of tau and thus increases the phosphorylation of tau at specific sites. These findings suggest that SIRT1 may be a potential therapeutic target for treating tauopathies.