Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation

Todd J. Cohen, Brian H. Constance, Andrew W. Hwang, Michael James, Chao Xing Yuan

Research output: Contribution to journalArticle

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Abstract

Tau proteins are abnormally aggregated in a range of neurodegenerative tauopathies including Alzheimer's disease (AD). Recently, tau has emerged as an extensively post-translationally modified protein, among which lysine acetylation is critical for normal tau function and its pathological aggregation. Here, we demonstrate that tau isoforms have different propensities to undergo lysine acetylation, with auto-acetylation occurring more prominently within the lysine-rich microtubule-binding repeats. Unexpectedly, we identified a unique intrinsic property of tau in which auto-acetylation induces proteolytic tau cleavage, thereby generating distinct N- and C-terminal tau fragments. Supporting a catalytic reaction-based mechanism, mapping and mutagenesis studies showed that tau cysteines, which are required for acetyl group transfer, are also essential for auto-proteolytic tau processing. Further mass spectrometry analysis identified the C-terminal 2nd and 4th microtubule binding repeats as potential sites of auto-cleavage. The identification of acetylationmediated auto-proteolysis provides a new biochemical mechanism for tau self-regulation and warrants further investigation into whether auto-catalytic functions of tau are implicated in AD and other tauopathies.

LanguageEnglish (US)
Article numbere0158470
JournalPloS one
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2016

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Acetylation
acetylation
automobiles
Tauopathies
Lysine
Microtubules
lysine
Alzheimer Disease
Alzheimer disease
Proteolysis
tau Proteins
Mutagenesis
microtubules
Mass spectrometry
Cysteine
Mass Spectrometry
Protein Isoforms
biochemical mechanisms
Agglomeration
mutagenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cohen, T. J., Constance, B. H., Hwang, A. W., James, M., & Yuan, C. X. (2016). Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation. PloS one, 11(7), [e0158470]. DOI: 10.1371/journal.pone.0158470

Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation. / Cohen, Todd J.; Constance, Brian H.; Hwang, Andrew W.; James, Michael; Yuan, Chao Xing.

In: PloS one, Vol. 11, No. 7, e0158470, 01.07.2016.

Research output: Contribution to journalArticle

Cohen, TJ, Constance, BH, Hwang, AW, James, M & Yuan, CX 2016, 'Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation' PloS one, vol 11, no. 7, e0158470. DOI: 10.1371/journal.pone.0158470
Cohen TJ, Constance BH, Hwang AW, James M, Yuan CX. Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation. PloS one. 2016 Jul 1;11(7). e0158470. Available from, DOI: 10.1371/journal.pone.0158470
Cohen, Todd J. ; Constance, Brian H. ; Hwang, Andrew W. ; James, Michael ; Yuan, Chao Xing. / Intrinsic tau acetylation is coupled to auto-proteolytic tau fragmentation. In: PloS one. 2016 ; Vol. 11, No. 7.
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