PolyQ Proteins Interfere with Nuclear Degradation of Cytosolic Proteins by Sequestering the Sis1p Chaperone

• Published in: Cell Vol. 154; no. 1; pp. 134 - 145
• Main Authors: Park, Sae-Hun, Kukushkin, Yury, Gupta, Rajat, Chen, Taotao, Konagai, Ayano, Hipp, Mark S., Hayer-Hartl, Manajit, Hartl, F. Ulrich
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-07-2013
• Subjects: Cell Nucleus - metabolism; cytoplasmic inclusions; cytosol; Cytosol - metabolism; degradation; Fructose-Bisphosphatase - chemistry; Fructose-Bisphosphatase - metabolism; green fluorescent protein; HEK293 Cells; HSP40 Heat-Shock Proteins - metabolism; HSP72 Heat-Shock Proteins - metabolism; Humans; mammals; neurodegenerative diseases; nucleus; Peptides - metabolism; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - metabolism; Protein Folding; Proteolysis; proteomics; quality control; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Ubiquitination; yeasts
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.06.003

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.
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•PolyQ aggregation interferes with clearance of misfolded cytosolic proteins•This effect is not due to inhibition of ubiquitylation or proteasome function•The essential Hsp40 chaperone, Sis1p, is sequestered by polyQ aggregates•Sis1p delivers misfolded proteins into the nucleus for proteasomal degradation
PolyQ proteins impair the cell’s ability to clear misfolded proteins by binding and sequestering the Hsp40 chaperone Sis1p, which is required for transporting misfolded proteins to the nucleus for proteasomal degradation.