Cited by 145Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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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·2017·Journal of Biological Chemistry

DOI 10.1074/jbc.m117.794602PMC PMC5602388

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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 .

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Figure 1. Pseudoacetylation of Lys-321 inhibits tau aggregation. a, WT and pseudoacetylated mutant KXGS recombinant tau proteins (K259Q/K290Q/K321Q/K353Q (4KQ) and K290Q/K321Q (2KQ)) were incubated with dextran sulfate to stimulate polymerization, which was detected by thioflavin S. The single K321Q mutant and the compound K290Q/K321Q and K259Q/K290Q/K321Q/K353Q mutants, which both include the K321Q mutation, exhibited the greatest inhibition of tau aggregation. b, acetylation-mimicking mutations were introduced on non-KXGS sites, and polymerization induced by dextran sulfate and detected by thioflavin S was compared with WT tau. All data are presented as mean ± S.D. ****, p < 0.0001; ***, p < 0.001; *, p < 0.05.CC BY · PubMed Central

Figure 2. Acetylation state of Lys-321 regulates tau filament formation. a–c, EM was used to compare dextran-sulfate induced filament assembly of WT tau (a) with mutant K321Q (b) or K321R (c) tau proteins. d–f, quantitation of EM analysis demonstrated that whereas the average length of WT and K321Q/R tau filaments per field was not different (F = 0.38, p = 0.69) (d), the total filament length per field (F = 47.9, p < 0.0001) (e) and the average number of filaments per field (F = 54.22, p < 0.0001) (f) were significantly reduced with K321Q mutant tau. All data are presented as mean ± S.D. (error bars). ****, p < 0.0001.CC BY · PubMed Central

Figure 3. Pseudoacetylation of Lys-321 prevents phosphorylation of Ser-324, which inhibits tau function. a, schematic diagram illustrating the location of the K321Q mutation within the third microtubule binding repeat domain (R3). b, HEK293T cells were cotransfected with WT or K321Q tau along with either GFP or MARK2, as indicated. Cell lysates were then prepared, and phosphorylation of KXGS motifs was evaluated by immunoblot. c, the impact of Ser-324 phosphorylation on tau function was assessed by monitoring microtubule assembly in the presence of WT and pseudophosphorylated (S324D/E) and dephosphorylated (S324A) mutant tau proteins. Error bars, S.D.CC BY · PubMed Central

Figure 4. Phosphorylation of Ser-324 is detected in the AAV model of tauopathy. a–f, representative images demonstrating the absence of pSer-324 immunolabeling in GFP-AAV–injected mice (a and b), whereas pSer-324–positive tau species are detected in TauP301L-AAV–injected mice in both the cortex (c) and CA1 field of the hippocampus (d), which exhibit high levels of human tau expression in this model (e and f). See Ref. 13 for additional details regarding the characterization of this model. Scale bar, 50 μm.CC BY · PubMed Central

Figure 5. Phosphorylation of Ser-324 in AD brain. a, pSer-324, 12E8 (pSer-262/356), and total human tau (E1) levels in frontal cortex from patients with AD compared with control cases were monitored by immunoblotting. b–e, immunohistochemistry was used to evaluate pSer-324 in paraffin-embedded tissue sections from the cortex of control (b) and AD patients (c–e). Scale bar, 50 μm.CC BY · PubMed Central

Figure 6. HDAC6 inhibition reduces pSer-324 in primary neuronal cultures. a, pSer-324, total human tau (E1), acetylated tubulin, and GAPDH levels were monitored by immunoblotting lysates prepared from primary neurons transduced with P301L-AAV. b, quantitation of the pSer-324–positive signal was normalized to total human tau (E1) to control for changes in tau levels. The experiment was repeated three times in duplicate (see supplemental Fig. S6), and statistical significance was assessed by Student's t test (t = 4.906, p = 0.0006). c, changes in total human tau levels were assessed by quantifying E1 immunoreactivity normalized to GAPDH to control for protein loading (t = 3.679, p = 0.004). d, inhibition of HDAC6 following ACY-738 treatment was monitored by evaluating acetylation of tubulin, which was normalized to GAPDH to control for protein loading (t = 13.65, p < 0.0001). Error bars, S.D.CC BY · PubMed Central

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Tau protein isoforms, phosphorylation and role in neurodegenerative disorders11These authors contributed equally to this work.
Buée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,142
Cryo-EM structures of tau filaments from Alzheimer’s disease
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“Whereas the increasing burden of tau pathology correlates with cognitive dysfunction and continues to progress with disease severity (3), both the pathogenic species of tau and the mechanism of toxicity remain unclear.”
Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease
Augustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998 · cited 2×
“Phosphorylation of tau on KIGS motifs (pSer-262/356) is observed at early stages of neurofibrillary tangle (NFT) formation in AD (14), but assessment of pSer-324 immunoreactivity in AD has not been performed.”
Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
Min, S.-W., Cho, S.-H., Zhou, Y., Schroeder, S., Haroutunian, V., Seeley, W. W., Huang, E. J., Shen, Y., Masliah, E., Mukherjee, C., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.044 · Cited by 949 · cited 1×
“which tau acetylation inhibits turnover and leads to accumulation (34), given that insoluble tau species purified from NFTs have been shown to be ubiquitinated (33), a lack of sufficient ubiquitination alone does not appear to be adequate to account for tau accumulation in disease.”
Biochemistry and Cell Biology of Tau Protein in Neurofibrillary DegenerationPreprint
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“4–6).”
Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding
Biernat, J., Gustke, N., Drewes, G., Mandelkow, E., & Mandelkow, E. (1993) · Neuron · doi:10.1016/0896-6273(93)90279-z · Cited by 796 · cited 2×
“Given that phosphorylation of Ser-262 in tau’s first KIGS motif has also been shown to impair tau’s ability to promote microtubule assembly (11), the phosphorylation status of all K X GS motifs may act to regulate tau function.”
The acetylation of tau inhibits its function and promotes pathological tau aggregation
Cohen, T. J., Guo, J. L., Hurtado, D. E., Kwong, L. K., Mills, I. P., Trojanowski, J. Q., & Lee, V. M. Y. (2011) · Nature Communications · doi:10.1038/ncomms1255 · Cited by 724 · cited 6×
“However, because acetylation of Lys-321 was not detected following CBP-mediated acetylation when increased aggregation was observed (18) (see supplemental Table S1 for a comparison of results across studies) but was identified under conditions that reduced aggregation (10), this supports our finding that modification…”
Influential
CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
Petrucelli, L. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh083 · Cited by 723
Self-citation
The high-affinity HSP90–CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
Dickey, C. A., Kamal, A., Lundgren, K., Klosak, N., Bailey, R. M., Dunmore, J., Ash, P., Shoraka, S., Zlatkovic, J., Eckman, C. B., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29715 · Cited by 642 · cited 1×
“In addition, tau species phosphorylated on Ser-262/356 are required for the synaptic toxicity of oligomeric A (25, 26), are unable to bind and stabilize microtubules (11, 27–29), and are also not recognized by the HSP chaperone network (30, 31).”
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THE REGULATION OF TAU PATHOGENESIS IN NEURODEGENERATION
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The acetylation of tau inhibits its function and promotes pathological tau aggregation
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Authors: Carlomagno, Y., Chung, D.-E. C., Yue, M., Castanedes-Casey, M., Madden, B. J., Dunmore, J., Tong, J., DeTure, M., Dickson, D. W., Petrucelli, L., & Cook, C.
Affiliations: Mayo Clinic (US)
Corresponding author: Petrucelli, Leonard
Cook, Casey
ORCID: Carlomagno, Yari
Chung, Dah-eun Chloe
Madden, Benjamin J.
DeTure, Michael
Dickson, Dennis W.
Petrucelli, Leonard
Cook, Casey
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2017-09
Volume: 292
Issue: 37
Pages: 15277-15286
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m117.794602
PMC: PMC5602388
OpenAlex: W2741056309
Cited by: 143
References: 36
Citations by year: 2026: 19 · 2025: 14 · 2024: 14 · 2023: 8 · 2022: 11 · 2021: 24 · 2020: 17 · 2019: 19 · 2018: 17
FWCI: 10.73
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 1098 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: BrightFocus Foundation (A2013546S)
National Institute of Neurological Disorders and Stroke (U54NS100693, R35NS097273, R01NS089544, R21NS094489)
National Institute on Aging (ADRC 2 P50 AG016574–16)
Mayo Clinic
Liston Family Foundation
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: tau protein, acetylation, phosphorylation, HDAC6, tau aggregation, microtubule stabilization, tauopathy, Alzheimer's disease
MeSH terms: Histone Deacetylase 6, Acetylation, Aged, Alzheimer Disease, Animals, Animals, Newborn, Cells, Cultured, Cerebral Cortex, Female, Histone Deacetylases, Humans, Lysine, Male, Mice, Transgenic, Mutation, Neurons, Phosphorylation, Protein Processing, Post-Translational, Serine, Tissue Banks, tau Proteins, Amino Acid Substitution, Tauopathies, Histone Deacetylase Inhibitors

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

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