Tau acetylation at K280 regulates tau phosphorylation

Abstract

Purpose/aim of the study

Accumulation of hyperphosphorylated tau is a key pathological finding of Alzheimer’s disease. Recently, acetylation of tau is emerging as another key pathogenic modification, especially regarding the acetylation of tau at K280 of the hexapeptide ²⁷⁵VQIINK²⁸⁰, a critical sequence in driving tau aggregation. However, the relationship between these two key post-translational modifications is not well known. In this study, effect of acetylation of tau at K280 on tau phosphorylation profile was investigated.

Materials and methods

The human neuroblastoma cell line, SH-SY5Y, was transfected with p300 acetyltransferase and tau to induce acetylation of tau. Phosphorylation profile after acetylation was evaluated on western blot. K280A-mutant tau was transfected to investigate the effect of acetylation of tau at K280 on tau phosphorylation profile.

Results

Overexpression of p300 acetyltransferase in tau-transfected SH-SY5Y human neuroblastoma cells increased acetylation of tau. Meanwhile, tau and its phosphorylation also increased at various sites such as S199/202, S202/T205, T231, and S422, but not at S396. However, blocking acetylation only at K280 with K280A-mutant tau reversed the increased phosphorylation of tau at S202/T205, T231, and S422, but not at S199/202 or S396.

Conclusion

Here we identified tau phosphorylation profile in the context of p300-induced acetylation and K280A-mutant tau, demonstrating that tau acetylation affects phosphorylation differently by residues and that acetylation at K280 is a determinant of phosphorylation at some residues in the context of pathologic acetyltransferase activity. Yet, our results suggest there is a complex interplay yet to be explored between tau acetylation with tau phosphorylation.

Keywords:

• Alzheimer’s disease
• tauopathy
• tau
• tau acetylation
• tau phosphorylation

Disclosure statement

No potential conflict of interest was reported by the author(s). MSK and YSM are employees of ADEL and DHK and SYY own stocks of ADEL.

Additional information

Funding

This study was supported by the Basic Science Research Program of the Ministry of Science, ICT, and Future Planning (grant no. 2018R1A5A2020732) and by Asan Life Science Institute (grant no. 2019IL0067).