Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing
The proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contr...
Main Authors: | , , , |
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Format: | Article |
Language: | English |
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eLife Sciences Publications Ltd
2014-12-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/04288 |
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author | Courtney L Klaips Megan L Hochstrasser Christine R Langlois Tricia R Serio |
author_facet | Courtney L Klaips Megan L Hochstrasser Christine R Langlois Tricia R Serio |
author_sort | Courtney L Klaips |
collection | DOAJ |
description | The proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance. However, other limitations imposed by the cellular environment are poorly understood. To identify cell-based restrictions on proteostasis capacity, we determined the mechanism by which thermal stress cures the [PSI+]/Sup35 prion. Remarkably, Sup35 amyloid is disassembled at elevated temperatures by the molecular chaperone Hsp104. This process requires Hsp104 engagement with heat-induced non-prion aggregates in late cell-cycle stage cells, which promotes its asymmetric retention and thereby effective activity. Thus, cell division imposes a potent limitation on proteostasis capacity that can be bypassed by the spatial engagement of a quality control factor. |
first_indexed | 2024-04-12T02:16:57Z |
format | Article |
id | doaj.art-a7c6fcafd29c45ac86b146c935c6a041 |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-12T02:16:57Z |
publishDate | 2014-12-01 |
publisher | eLife Sciences Publications Ltd |
record_format | Article |
series | eLife |
spelling | doaj.art-a7c6fcafd29c45ac86b146c935c6a0412022-12-22T03:52:13ZengeLife Sciences Publications LtdeLife2050-084X2014-12-01310.7554/eLife.04288Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curingCourtney L Klaips0Megan L Hochstrasser1Christine R Langlois2Tricia R Serio3Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United States; Department of Molecular and Cellular Biology, University of Arizona, Tucson, United StatesDepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United StatesDepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, United StatesDepartment of Molecular and Cellular Biology, University of Arizona, Tucson, United StatesThe proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance. However, other limitations imposed by the cellular environment are poorly understood. To identify cell-based restrictions on proteostasis capacity, we determined the mechanism by which thermal stress cures the [PSI+]/Sup35 prion. Remarkably, Sup35 amyloid is disassembled at elevated temperatures by the molecular chaperone Hsp104. This process requires Hsp104 engagement with heat-induced non-prion aggregates in late cell-cycle stage cells, which promotes its asymmetric retention and thereby effective activity. Thus, cell division imposes a potent limitation on proteostasis capacity that can be bypassed by the spatial engagement of a quality control factor.https://elifesciences.org/articles/04288chaperoneprotein misfoldingamyloidprion |
spellingShingle | Courtney L Klaips Megan L Hochstrasser Christine R Langlois Tricia R Serio Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing eLife chaperone protein misfolding amyloid prion |
title | Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing |
title_full | Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing |
title_fullStr | Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing |
title_full_unstemmed | Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing |
title_short | Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing |
title_sort | spatial quality control bypasses cell based limitations on proteostasis to promote prion curing |
topic | chaperone protein misfolding amyloid prion |
url | https://elifesciences.org/articles/04288 |
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