PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone

Cell. 2013 Jul 3;154(1):134-45. doi: 10.1016/j.cell.2013.06.003. Epub 2013 Jun 20.


Dysfunction of protein quality control contributes to the cellular pathology of polyglutamine (polyQ) expansion diseases and other neurodegenerative disorders associated with aggregate deposition. Here we analyzed how polyQ aggregation interferes with the clearance of misfolded proteins by the ubiquitin-proteasome system (UPS). We show in a yeast model that polyQ-expanded proteins inhibit the UPS-mediated degradation of misfolded cytosolic carboxypeptidase Y(∗) fused to green fluorescent protein (GFP) (CG(∗)) without blocking ubiquitylation or proteasome function. Quantitative proteomic analysis reveals that the polyQ aggregates sequester the low-abundant and essential Hsp40 chaperone Sis1p. Overexpression of Sis1p restores CG(∗) degradation. Surprisingly, we find that Sis1p, and its homolog DnaJB1 in mammalian cells, mediates the delivery of misfolded proteins into the nucleus for proteasomal degradation. Sis1p shuttles between cytosol and nucleus, and its cellular level limits the capacity of this quality control pathway. Upon depletion of Sis1p by polyQ aggregation, misfolded proteins are barred from entering the nucleus and form cytoplasmic inclusions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • Fructose-Bisphosphatase / chemistry
  • Fructose-Bisphosphatase / metabolism
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP72 Heat-Shock Proteins / metabolism
  • Humans
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Folding*
  • Proteolysis*
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Ubiquitination


  • DNAJB1 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP72 Heat-Shock Proteins
  • Peptides
  • SIS1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • polyglutamine
  • Fructose-Bisphosphatase
  • Proteasome Endopeptidase Complex