The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington's disease patients

Nat Commun. 2018 Jul 23;9(1):2886. doi: 10.1038/s41467-018-05320-3.


Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington's disease (HD). Here we show that proteasome activity determines HTT levels, preventing polyQ-expanded aggregation in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit high levels of UBR5, a ubiquitin ligase required for proteasomal degradation of both normal and mutant HTT. Conversely, loss of UBR5 increases HTT levels and triggers polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens polyQ-expanded aggregation and neurotoxicity in invertebrate models. Notably, UBR5 overexpression induces polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD-cell models. Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a modulator of super-vigilant proteostasis of iPSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Caenorhabditis elegans
  • Cell Differentiation
  • Genetic Variation
  • Genotype
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Mutation
  • Neurons / metabolism
  • Peptides / metabolism
  • Pluripotent Stem Cells / metabolism*
  • Polymorphism, Single Nucleotide
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Denaturation
  • Protein Folding
  • Proteomics
  • Proteostasis
  • Ubiquitin-Protein Ligases / genetics*


  • Amyloid beta-Peptides
  • HTT protein, human
  • Huntingtin Protein
  • Peptides
  • polyglutamine
  • UBR5 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex