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Misfolded proteins partition between two distinct quality control compartments

Nature volume 454, pages 1088–1095 (2008)Cite this article

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.

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Figure 1: A panel of quality control substrates defines two distinct compartments for the sequestration of misfolded cytosolic proteins.
Figure 2: Amyloidogenic proteins are preferentially directed to a single inclusion.
Figure 3: Mammalian cells differentially sequester misfolded proteins in two distinct compartments.
Figure 4: Differential solubility of misfolded substrates in the distinct quality control compartments.
Figure 6: Partitioning between JUNQ and IPOD is regulated by ubiquitination.
Figure 5: The JUNQ and IPOD are defined subcellular compartments.

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Acknowledgements

We thank R. Tsien, S. Michaelis, J. Glover, C. Enenkel and V. Albanese for reagents; J. Mulholland for electron microscopy and deconvolution microscopy help; S. Yamada and W. J. Nelson for help with the live cell microscopy. We thank R. Andino, W. Burkholder, J. England, R. Geller, M. Kaganovich, E. Bennett, J. Nelson and members of the Frydman laboratory for discussions and comments on the manuscript. This work was supported by grants from NIH to R.K. and J.F.

Author Contributions J.F. directed the project; D.K. and J.F. designed and interpreted all experiments; R.K. participated in the initial fluorescence microscopy experiments; D.K. performed all experiments. D.K. and J.F. wrote the paper.

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  1. Department of Biology and BioX Program, Stanford University, Stanford, California 94305, USA,

    Daniel Kaganovich, Ron Kopito & Judith Frydman

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  1. Daniel Kaganovich
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Correspondence to Judith Frydman.

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Kaganovich, D., Kopito, R. & Frydman, J. Misfolded proteins partition between two distinct quality control compartments. Nature 454, 1088–1095 (2008). https://doi.org/10.1038/nature07195

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