title: The microtubule-associated tau protein has intrinsic acetyltransferase activity.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. toddcohe@upenn.edu
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
authors.forename: Dave
authors.initials: D
authors.lastname: Friedmann
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Hwang
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D007700:Kinetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000201:enzymology*; D011485:Protein Binding; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D000123:Acetyltransferases; D008239:Lysine; D003545:Cysteine