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
N1 - Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/9/15
Y1 - 2017/9/15
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.
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U2 - 10.1074/jbc.M117.794602
DO - 10.1074/jbc.M117.794602
M3 - Article
C2 - 28760828
AN - SCOPUS:85029591600
SN - 0021-9258
VL - 292
SP - 15277
EP - 15286
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -