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

Park, S.-H., Kukushkin, Y., Gupta, R., Chen, T., Konagai, A., Hipp, M. S., et al. (2013). PolyQ Proteins Interfere with Nuclear Degradation of Cytosolic Proteins by Sequestering the Sis1p Chaperone. Cell, 154(1), 134-145. doi:10.1016/j.cell.2013.06.003.

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 Creators:
Park, Sae-Hun1, Author              
Kukushkin, Yury1, Author              
Gupta, Rajat1, Author              
Chen, Taotao1, Author              
Konagai, Ayano1, Author              
Hipp, Mark S.1, Author              
Hayer-Hartl, Manajit2, Author              
Hartl, F. Ulrich1, Author              
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2Hayer-Hartl, Manajit / Chaperonin-assisted Protein Folding, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565153              

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 Abstract: 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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Language(s): eng - English
 Dates: 2013-07-03
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.cell.2013.06.003
 Degree: -

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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 154 (1) Sequence Number: - Start / End Page: 134 - 145 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183