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An acetylation–phosphorylation switch that regulates tau aggregation propensity and function
Open accessAbstract
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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“while increased Tau acetylation reduces Tau phosphorylation [34, 42].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [42]
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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.”
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“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
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“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).”
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“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…”
InfluentialCHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
Petrucelli, L. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh083 · Cited by 723
Self-citationDickey, 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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Items 101–145 of 145
Modulation of Primary and Secondary Processes in Tau Fibril Formation by Salt-Induced Dynamics
Vahid, A. A., Hassan, M. S. O., Sahayaraj, A. E., Babu, A. T., Kizhakkeduth, S. T., & Vijayan, V. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00852 · Cited by 6
Tauopathy in AD: Therapeutic Potential of MARK-4
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Hassan, M. S. O., Vahid, A. A., Sahayaraj, A. E., Viswanathan, R., & Vijayan, V. (2023) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.3c00912 · Cited by 5
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“In a follow-on study, ac-K321 was identified as another site for HDAC6-mediated deacetylation and was shown to be essential for inhibiting tau aggregation in vitro and preventing phosphorylation of downstream serine 324 (12).”
BackgroundChi, H., Sang, T., & Chang, H.-Y. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.73198 · Cited by 5
“This observation leads to an intriguing prospect that some switches from acetylation to phosphorylation might affect disease progression [144].”
BackgroundTau seeding activity in Alzheimer's disease: Characteristics, factors, and applications
Liu, Y., Chen, Y., Chen, Z., Wan, H., & Wu, C. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251378772 · Cited by 4
“Interestingly, acetylation at Lys321 inhibits fi lament nucleation but not elongation, 58 though its impact on tau seeding remains unclear.”
Methods for studying the effects of phosphorylation patterns in proteins
Bressler, S., Grunhaus, D., Hurevich, M., & Friedler, A. (2026) · Biochemical Society Transactions · doi:10.1042/bst20250137 · Cited by 3
Post-translational modifications as a regulatory code for tau function in health and disease
Nordbeck, A. J., Sharma, B., Garcia, C. A., & Tseng, J. (2026) · Frontiers in Dementia · doi:10.3389/frdem.2026.1834737 · Cited by 3
“For example, acetylation at K321 has been shown to block phosphorylation at S324, indicating that certain acetylation events may counteract phosphorylation-dependent toxicity (Carlomagno et al., 2017).”
Probing tau citrullination in Alzheimer’s disease brains and mouse models of tauopathy
Liang, H., Hunt, J. B., Ma, C., Kovalenko, A., Calahatian, J. I. T., Pedersen, C., Liu, H., Li, J., Serrano, M., Blazier, D. M., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02965-5 · Cited by 3
“Given the dynamic complexity of PTMs in tauopathies [9, 16, 48], it is plausible that less well-studied modifications add to tau diversity and contribute to subtypes of the clinical spectrum.”
Santini, A., Tassinari, E., Altomare, A., Loi, M., Ciani, E., Trazzi, S., Piccarducci, R., Daniele, S., Martini, C., Pagliarani, B., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117838 · Cited by 5
CTE-type tau filaments in Alzheimer’s disease with co-morbid LATE-NC
Rana, J. K., Pinarbasi, E. S., Fernandez, M. G., Navratna, V., Conway, K. S., Lieberman, A. P., Barmada, S. J., & Mosalaganti, S. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-03052-z · Cited by 2
“A critical difference lies in the residue S324, which is buried within the protofilament interface in CTE-fold type I, whereas it is exposed and phosphorylated in AD-fold tau 37,44 .”
Tambe, V., Niyonshuti, P., Aditya, V., Hays, F. A., Kayesh, R., Soderblom, E. J., Xu, C., & Yue, W. (2026) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2026.100246 · Cited by 2
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Mass spectrometry structural analysis of intrinsically disordered phosphoproteins
Lantz, C., Zenaidee, M. A., Tran, D. P., Biggs, K. E., Bitan, G., Loo, R. R. O., & Loo, J. A. (2025) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2025.117455 · Cited by 1
Impact of Lysine Acetylation Mutations on the Structure of Full-Length Tau Fibrils
Dregni, A. J., & Hong, M. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00149 · Cited by 1
Regulation of organic anion transporting polypeptide 1B1 transport function by lysine deacetylase 6
Aditya, V., Tambe, V., Niyonshuti, P., Kayesh, R., Soderblom, E. J., Zhang, X. M., Xu, C., & Yue, W. (2026) · Molecular Pharmacology · doi:10.1016/j.molpha.2026.100132 · Cited by 2
Regulation | Post Translational Modifications by Succinylation and Acetylation
Acosta, D. M., Eliezer, D., & Gibson, G. E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00137-7 · Cited by 1
Single Molecule Imaging Reveals Tau Structure And Function On The Microtubule Surface
Stern, J. L. (2018) · ScholarWorks -A service of University of Vermont Libraries (University of Vermont)
The amyloidogenic properties of the CAP superfamily proteins
Sheng, J. (2020) · Utrecht University Repository (Utrecht University) · doi:10.33540/530
Linking histone deacetylases and phosphodiesterase 5 in novel treatments for Alzheimer's disease
García‐Osta, A., & Cuadrado‐Tejedor, M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815868-5.00014-1
THE ROLE OF MICROTUBULE-ASSOCIATED PROTEIN TAU IN NEURONAL EXCITABILITY AND EPILEPTOGENESIS
Cloyd, R. (2021) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2021.271
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“Also, tau acetylation modulates its turnover (Caballero et al., 2021; Choi et al., 2020; Cook et al., 2014; Min et al., 2015) and affects its aggregation (Carlomagno et al., 2017; Cohen et al., 2011).”
BackgroundMorgado, J., Diniz, L. P., Araújo, A. P. B., Antônio, L. M. D. S., Mota-Araujo, H. P., Pinheiro, P. D. S. M., Sagrillo, F. S., Vargas, G., Ferreira, S. T., Figueiredo, C. P., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.25.564038
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Caractérisation d'anticorps à domaine unique dirigés contre la protéine Tau
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“Récemment, Carlomagno et ses collaborateurs ont proposé un mécanisme dans lequel l’acétylation de Tau pourrait inhiber la phosphorylation spécifique de certains résidus, et ainsi contribuer à inhiber son agrégation (Carlomagno et al., 2017). iii.”
BackgroundAge-dependent remodelling of RNP condensates in Drosophila neurons
Pushpalatha, K. V. (2021) · theses.fr (ABES) · doi:10.70675/ea7eb43bz5222z4a4fza2a6zafb2ac0101f9
Molecular grammar of biomolecular condensate formation
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Therapeutic strategies for Tau and Alzheimer’s disease
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“For instance, acetylation at K321 inhibits Tau aggregation and prevents phosphorylation on S324 residue, uncovering a novel acetylation–phosphorylation switch at K321/S324 that regulates Tau polymerization and can be pharmacologically modulated by HDAC inhibitors [15].”
Chen, Y., Ge, L., Lazarovici, P., & Zheng, W. (2026) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x26500667
Basavaraju, K., K, H. D., & G., P. P. C. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.09.012
A complex of MAST1 and 14-3-3η regulates Tau phosphorylation in the developing cortex
Antonioli, S., Heisterkamp, P., Chen, W., Anrather, D., Hartl, M., Martínez-Reza, M. F., Tripathy, R., Schutzbier, M., Mechtler, K., Keays, D. A., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2617534123
“Our data demonstrate that at least in vitro, MAST1 is capable of phosphorylating Tau on S262, S324 and S356, all of which are reported phosphosites that inhibit microtubule binding (54–56).”
Basavaraju, K. C., & G., P. P. C. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154717
Balmik, A. A., & Khanal, P. (2026) · Advances in pharmacology · doi:10.1016/bs.apha.2026.08.002
Metadata
- 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
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 292
- Issue
- 37
- Pages
- 15277-15286
- ISSN
- 0021-9258 (ISSN-L)
- 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
- 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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