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

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Park,  Sae-Hun
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Kukushkin,  Yury
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Gupta,  Rajat
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Chen,  Taotao
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Konagai,  Ayano
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Hipp,  Mark S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Hayer-Hartl,  Manajit
Hayer-Hartl, Manajit / Chaperonin-assisted Protein Folding, Max Planck Institute of Biochemistry, Max Planck Society;

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Hartl,  F. Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0013-F9F0-4
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.