The proteasome activators Blm10/PA200 enhance the proteasomal degradation of N-terminal huntingtin

Azzam Aladdin, Yanhua Yao*, Ciyu Yang, Günther Kahlert, Marvi Ghani, Nikolett Király, Anita Boratkó, Karen Uray, Gunnar Dittmar, Krisztina Tar

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin-and ATP-independent manner. Furthermore, PA200 also participates in the degradation of acetylated histones. In our study, we use a combination of yeast and human cell systems to investigate the role of Blm10/PA200 in the degradation of N-terminal Huntingtin fragments (N-Htt). We demonstrate that the human PA200 binds to N-Htt. The loss of Blm10 in yeast or PA200 in human cells results in increased mutant N-Htt aggregate formation and elevated cellular toxicity. Furthermore, Blm10 in vitro accelerates the proteasomal degradation of soluble N-Htt. Collectively, our data suggest N-Htt as a new substrate for Blm10/PA200-proteasomes and point to new approaches in Huntington’s disease (HD) research.

Original languageEnglish
Article number1581
Pages (from-to)1-32
Number of pages32
JournalBiomolecules
Volume10
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Degradation
  • Huntingtin protein (Htt), Blm10/PA200-proteasomes
  • Huntington’s disease
  • Mutant N-Htt aggregates
  • Soluble N-Htt

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