An acetylation-phosphorylation switch that regulates tau aggregation propensity and function

J Biol Chem. 2017 Sep 15;292(37):15277-15286. doi: 10.1074/jbc.M117.794602. Epub 2017 Jul 31.


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 in vitro 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 in vitro 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 in vivo.

Keywords: Alzheimer disease; Tau protein (Tau); acetylation; aggregation; histone deacetylase 6 (HDAC6); neurodegenerative disease; phosphorylation; tauopathy.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Aged
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amino Acid Substitution
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Female
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Lysine / metabolism
  • Male
  • Mice, Transgenic
  • Mutation
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational* / drug effects
  • Serine / metabolism
  • Tauopathies / drug therapy
  • Tauopathies / metabolism*
  • Tauopathies / pathology
  • Tissue Banks
  • tau Proteins / chemistry
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Histone Deacetylase Inhibitors
  • tau Proteins
  • Serine
  • HDAC6 protein, human
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases
  • Lysine