An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function

Yari Carlomagno, Dah eun Chloe Chung, Mei Yue, Monica Castanedes-Casey, Benjamin J. Madden, Judy Dunmore, Jimei Tong, Michael Deture, Dennis W Dickson, Leonard Petrucelli, Casey Cook

Research output: Contribution to journalArticle

35 Scopus citations

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 demen-tias. 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–phos-phorylation 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.

Original languageEnglish (US)
Pages (from-to)15277-15286
Number of pages10
JournalJournal of Biological Chemistry
Volume292
Issue number37
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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