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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

1
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224.
2
the Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, Florida 32224, and.
3
the Medical Genome Facility Proteomics Core, Mayo Clinic, Rochester, Minnesota 55905.
4
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, petrucelli.leonard@mayo.edu.
5
From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, cook.casey@mayo.edu.

Abstract

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

PMID:
28760828
PMCID:
PMC5602388
DOI:
10.1074/jbc.M117.794602
[Indexed for MEDLINE]
Free PMC Article

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