Title

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

Journal

The Journal of biological chemistry

Volume

292

Issue

None

Pages

15277-15286

Date

2017-09-15

Authors

Carlomagno Y | Castanedes-Casey M | Chung DC | Cook C | DeTure M | Dickson DW | Dunmore J | Madden BJ | Petrucelli L | Tong J | Yue M

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. 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.

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6).

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