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Misfolded proteins partition between two distinct quality control compartments

Author

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  • Daniel Kaganovich

    (Stanford University, Stanford, California 94305, USA)

  • Ron Kopito

    (Stanford University, Stanford, California 94305, USA)

  • Judith Frydman

    (Stanford University, Stanford, California 94305, USA)

Abstract

The accumulation of misfolded proteins in intracellular amyloid inclusions, typical of many neurodegenerative disorders including Huntington’s and prion disease, is thought to occur after failure of the cellular protein quality control mechanisms. Here we examine the formation of misfolded protein inclusions in the eukaryotic cytosol of yeast and mammalian cell culture models. We identify two intracellular compartments for the sequestration of misfolded cytosolic proteins. Partition of quality control substrates to either compartment seems to depend on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins accumulate in a juxtanuclear compartment where proteasomes are concentrated. In contrast, terminally aggregated proteins are sequestered in a perivacuolar inclusion. Notably, disease-associated Huntingtin and prion proteins are preferentially directed to the perivacuolar compartment. Enhancing ubiquitination of a prion protein suffices to promote its delivery to the juxtanuclear inclusion. Our findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease.

Suggested Citation

  • Daniel Kaganovich & Ron Kopito & Judith Frydman, 2008. "Misfolded proteins partition between two distinct quality control compartments," Nature, Nature, vol. 454(7208), pages 1088-1095, August.
  • Handle: RePEc:nat:nature:v:454:y:2008:i:7208:d:10.1038_nature07195
    DOI: 10.1038/nature07195
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    Cited by:

    1. Arthur Fischbach & Angela Johns & Kara L. Schneider & Xinxin Hao & Peter Tessarz & Thomas Nyström, 2023. "Artificial Hsp104-mediated systems for re-localizing protein aggregates," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Anne-Sophie Coquel & Jean-Pascal Jacob & Mael Primet & Alice Demarez & Mariella Dimiccoli & Thomas Julou & Lionel Moisan & Ariel B Lindner & Hugues Berry, 2013. "Localization of Protein Aggregation in Escherichia coli Is Governed by Diffusion and Nucleoid Macromolecular Crowding Effect," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-14, April.
    3. Arun Kumar & Veena Mathew & Peter C. Stirling, 2024. "Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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