TitleAn acetylation-phosphorylation switch that regulates tau aggregation propensity and function.
Publication TypeJournal Article
Year of Publication2017
AuthorsCarlomagno Y, Chung D-EChloe, Yue M, Castanedes-Casey M, Madden BJ, Dunmore J, Tong J, DeTure M, Dickson DW, Petrucelli L, Cook C
JournalJ Biol Chem
Date Published2017 09 15
KeywordsAcetylation, Aged, Alzheimer Disease, Amino Acid Substitution, Animals, Animals, Newborn, Cells, Cultured, Cerebral Cortex, Female, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Lysine, Male, Mice, Transgenic, Mutation, Neurons, Phosphorylation, Protein Processing, Post-Translational, Serine, tau Proteins, Tauopathies, Tissue Banks

The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau's biophysical properties Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6-regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. Because the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer-324 in tau pathobiology and to determine whether therapeutically modulating this acetylation-phosphorylation switch affects disease progression .

Alternate JournalJ. Biol. Chem.
PubMed ID28760828
PubMed Central IDPMC5602388
Grant ListR35 NS097273 / NS / NINDS NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R21 NS094489 / NS / NINDS NIH HHS / United States
R01 NS089544 / NS / NINDS NIH HHS / United States
U54 NS100693 / NS / NINDS NIH HHS / United States