CHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments

Ji Hyeon Kim, Jeeyoung Lee, Won Hoon Choi, Seoyoung Park, Seo Hyeong Park, Jung Hoon Lee, Sang Min Lim, Ji Young Mun, Hyun Soo Cho, Dohyun Han, Young Ho Suh, Min Jae Lee

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10 Citations (Scopus)


The tau protein is a highly soluble and natively unfolded protein. Under pathological conditions, tau undergoes multiple post-translational modifications (PTMs) and conformational changes to form insoluble filaments, which are the proteinaceous signatures of tauopathies. To dissect the crosstalk among tau PTMs during the aggregation process, we phosphorylated and ubiquitylated recombinant tau in vitro using GSK3β and CHIP, respectively. The resulting phospho-ub-tau contained conventional polyubiquitin chains with lysine 48 linkages, sufficient for proteasomal degradation, whereas unphosphorylated ub-tau species retained only one-three ubiquitin moieties. Mass-spectrometric analysis of in vitro reconstituted phospho-ub-tau revealed seven additional ubiquitylation sites, some of which are known to stabilize tau protofilament stacking in the human brain with tauopathy. When the ubiquitylation reaction was prolonged, phospho-ub-tau transformed into insoluble hyperubiquitylated tau species featuring fibrillar morphology and in vitro seeding activity. We developed a small-molecule inhibitor of CHIP through biophysical screening; this effectively suppressed tau ubiquitylation in vitro and delayed its aggregation in cultured cells including primary cultured neurons. Our biochemical findings point to a "multiple-hit model,"where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process, thus indicating that targeting tau ubiquitylation may be an effective strategy to alleviate the course of tauopathies.

Original languageEnglish
Pages (from-to)5599-5610
Number of pages12
JournalChemical Science
Issue number15
Publication statusPublished - 2021 Apr 21

Bibliographical note

Publisher Copyright:
© 2021 The Royal Society of Chemistry.

All Science Journal Classification (ASJC) codes

  • Chemistry(all)


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