Abstract
Tau proteins are the building blocks of neurofibrillary tangles (NFTs) found in a range of neurodegenerative tauopathies, including Alzheimer's disease. Recently, we demonstrated that tau is extensively post-translationally modified by lysine acetylation, which impairs normal tau function and promotes pathological aggregation. Identifying the enzymes that mediate tau acetylation could provide targets for future therapies aimed at reducing the burden of acetylated tau. Here, we report that mammalian tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation. Functional mapping of tau acetyltransferase activity followed by biochemical analysis revealed that tau uses catalytic cysteine residues in the microtubule-binding domain to facilitate tau lysine acetylation, thus suggesting a mechanism similar to that employed by MYST-family acetyltransferases. The identification of tau as an acetyltransferase provides a framework to further understand tau pathogenesis and highlights tau enzymatic activity as a potential therapeutic target.
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Acknowledgements
We would like to thank T.P. Yao, J.Q. Trojanowski and L.K. Kwong for critical reading of this manuscript. We thank T.P. Yao (Duke University, Durham, North Carolina, USA) for kindly providing plasmids expressing a panel of histone acetyltransferases. We thank P. Seubert (Elan Pharmaceuticals, San Francisco, California, USA) for kindly providing anti-tau 12e8 antibody. We thank K. Brunden, A. Crowe, C. Li and other members of the Center for Neurodegenerative Disease Research for their technical support, helpful comments and critical suggestions. This study was supported by the US National Institutes of Health grants AG17586 (V.M.Y.L.) and GM060293 (R.M.) and the Association for Frontotemporal Degeneration (T.J.C.).
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T.J.C. and A.W.H. performed in vitro and cell-based acetylation experiments, mouse and human biochemical procedures and MS analysis, and T.J.C. was involved in the design and writing of this study. D.F. performed kinetic analysis of tau acetyltransferase activity and was involved in the writing of this study. V.M.Y.L. and R.M. supervised and designed the experiments and were involved in the writing of this study.
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Cohen, T., Friedmann, D., Hwang, A. et al. The microtubule-associated tau protein has intrinsic acetyltransferase activity. Nat Struct Mol Biol 20, 756–762 (2013). https://doi.org/10.1038/nsmb.2555
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DOI: https://doi.org/10.1038/nsmb.2555
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