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

28 Citations (Scopus)

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

Fingerprint

Phosphorylation
Acetylation
Histone Deacetylases
Agglomeration
Switches
Tauopathies
Microtubules
Alzheimer Disease
Neurodegenerative diseases
tau Proteins
Aptitude
Polymerization
Neurodegenerative Diseases
Disease Progression
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Carlomagno, Y., Chung, D. E. C., Yue, M., Castanedes-Casey, M., Madden, B. J., Dunmore, J., ... Cook, C. (2017). An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. Journal of Biological Chemistry, 292(37), 15277-15286. https://doi.org/10.1074/jbc.M117.794602

An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. / Carlomagno, Yari; Chung, Dah eun Chloe; Yue, Mei; Castanedes-Casey, Monica; Madden, Benjamin J.; Dunmore, Judy; Tong, Jimei; Deture, Michael; Dickson, Dennis W; Petrucelli, Leonard; Cook, Casey.

In: Journal of Biological Chemistry, Vol. 292, No. 37, 2017, p. 15277-15286.

Research output: Contribution to journalArticle

Carlomagno Y, Chung DEC, Yue M, Castanedes-Casey M, Madden BJ, Dunmore J et al. An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. Journal of Biological Chemistry. 2017;292(37):15277-15286. https://doi.org/10.1074/jbc.M117.794602
Carlomagno, Yari ; Chung, Dah eun Chloe ; Yue, Mei ; Castanedes-Casey, Monica ; Madden, Benjamin J. ; Dunmore, Judy ; Tong, Jimei ; Deture, Michael ; Dickson, Dennis W ; Petrucelli, Leonard ; Cook, Casey. / An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 37. pp. 15277-15286.
@article{9ac0f05e7e9e4c4086c422b4e5fb64ff,
title = "An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function",
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.",
author = "Yari Carlomagno and Chung, {Dah eun Chloe} and Mei Yue and Monica Castanedes-Casey and Madden, {Benjamin J.} and Judy Dunmore and Jimei Tong and Michael Deture and Dickson, {Dennis W} and Leonard Petrucelli and Casey Cook",
year = "2017",
doi = "10.1074/jbc.M117.794602",
language = "English (US)",
volume = "292",
pages = "15277--15286",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

TY - JOUR

T1 - An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function

AU - Carlomagno, Yari

AU - Chung, Dah eun Chloe

AU - Yue, Mei

AU - Castanedes-Casey, Monica

AU - Madden, Benjamin J.

AU - Dunmore, Judy

AU - Tong, Jimei

AU - Deture, Michael

AU - Dickson, Dennis W

AU - Petrucelli, Leonard

AU - Cook, Casey

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029591600&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029591600&partnerID=8YFLogxK

U2 - 10.1074/jbc.M117.794602

DO - 10.1074/jbc.M117.794602

M3 - Article

C2 - 28760828

AN - SCOPUS:85029591600

VL - 292

SP - 15277

EP - 15286

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -