Send to

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

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

Author information

From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
the Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida 32224, and.
the Medical Genome Facility Proteomics Core, Mayo Clinic, Rochester, Minnesota 55905.
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224,
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224,


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.


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

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center