A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

Cell Death Dis. 2021 Feb 2;12(2):136. doi: 10.1038/s41419-021-03444-x.


Polyglutamine (polyQ) diseases comprise Huntington's disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin-proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Ataxin-3 / genetics
  • Ataxin-3 / metabolism*
  • Cell Death
  • Cell Line, Tumor
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • HEK293 Cells
  • Humans
  • Machado-Joseph Disease / enzymology*
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / pathology
  • Neurons / enzymology*
  • Neurons / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Proteolysis
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*


  • Drosophila Proteins
  • EXOC7 protein, human
  • Nuclear Proteins
  • Peptides
  • Protein Aggregates
  • RNA Splicing Factors
  • Repressor Proteins
  • Vesicular Transport Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3
  • Proteasome Endopeptidase Complex
  • DNA Repair Enzymes
  • PRPF19 protein, human
  • Prp19 protein, Drosophila