Cytoprotective role of ubiquitin against toxicity induced by polyglutamine-expanded aggregates

Jin Sil Bae, Kwon Yul Ryu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Ubiquitin (Ub) homeostasis is important for cellular function and survival, especially under stress conditions. Recently, we have demonstrated that Ubc−/− (Ub-deficient) mouse embryonic fibroblasts (MEFs) exhibited reduced viability under oxidative stress induced by arsenite, which was not due to dysregulation of the antioxidant response pathway, but rather due to the potential toxicity caused by the misfolded protein aggregates. However, it is still not clear whether Ub deficiency is directly related to the accumulation of toxic protein aggregates, as arsenite itself triggers protein aggregation and renders cells into aberrant conditions such as reduced proteasome function and inhibition of autophagic flux. Therefore, under arsenite treatment, the outcome could be derived from the combination of multiple defective pathways. Furthermore, it has also been suggested that ubiquitination status of misfolded proteins may not be important for the formation of inclusion bodies composed of misfolded protein aggregates. We therefore wondered whether Ub deficiency is sufficient to trigger the accumulation of toxic protein aggregates inside the cells. In this study, we ectopically expressed polyQ-expanded aggregates (Q103) in MEFs and observed inclusion body formation at the juxtanuclear region, which was independent of cellular Ub levels. In contrast to arsenite treatment, polyQ expression did not affect proteasome function. However, we observed an increased accumulation of Q103 aggregates in Ubc−/− MEFs, which was due to impaired autophagic clearance. Finally, we demonstrated that the increased accumulation of Q103 aggregates under Ub deficiency dramatically reduced the viability of cells. Therefore, our results suggest that the maintenance of proper levels of cellular Ub is important to protect cells against the toxicity induced by the accumulation of protein aggregates.

Original languageEnglish
Pages (from-to)344-350
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume500
Issue number2
DOIs
StatePublished - 2 Jun 2018

Keywords

  • Aggregates
  • Autophagy
  • Polyglutamine
  • Proteasome
  • Toxicity
  • Ubiquitin

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