Misfolded proteins partition between two distinct quality control compartments

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 prot...

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Päätekijät: Kaganovich, Daniel, Kopito, Ron, Frydman, Judith
Aineistotyyppi: Artikkeli
Kieli:English
Julkaistu: 2008
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Linkit:https://ncbi.nlm.nih.gov/pmc/articles/PMC2746971/
https://ncbi.nlm.nih.gov/pubmed/18756251
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/nature07195
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spelling pubmed-27469712009-09-21 Misfolded proteins partition between two distinct quality control compartments Kaganovich, Daniel Kopito, Ron Frydman, Judith Nature Article 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. 2008-08-28 /pmc/articles/PMC2746971/ /pubmed/18756251 http://dx.doi.org/10.1038/nature07195 Text en
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Article
spellingShingle Article
Kaganovich, Daniel
Kopito, Ron
Frydman, Judith
Misfolded proteins partition between two distinct quality control compartments
description 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.
author Kaganovich, Daniel
Kopito, Ron
Frydman, Judith
author_facet Kaganovich, Daniel
Kopito, Ron
Frydman, Judith
author_sort Kaganovich, Daniel
title Misfolded proteins partition between two distinct quality control compartments
title_short Misfolded proteins partition between two distinct quality control compartments
title_full Misfolded proteins partition between two distinct quality control compartments
title_fullStr Misfolded proteins partition between two distinct quality control compartments
title_full_unstemmed Misfolded proteins partition between two distinct quality control compartments
title_sort misfolded proteins partition between two distinct quality control compartments
publishDate 2008
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2746971/
https://ncbi.nlm.nih.gov/pubmed/18756251
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/nature07195
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