Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing

Courtney L. Klaips, Megan L. Hochstrasser, Christine R. Langlois, Tricia R Serio

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournaleLife
Volume3
DOIs
StatePublished - 2014

Fingerprint

Prions
Amyloid
Quality Control
Quality control
Curing
Hot Temperature
Cells
Protein folding
Molecular Chaperones
Protein Folding
Thermal stress
Cell Division
Cell Cycle
Proteins
Temperature

Keywords

  • amyloid
  • cell biology
  • chaperone
  • prion
  • protein misfolding
  • S. cerevisiae

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing. / Klaips, Courtney L.; Hochstrasser, Megan L.; Langlois, Christine R.; Serio, Tricia R.

In: eLife, Vol. 3, 2014.

Research output: Contribution to journalArticle

Klaips, Courtney L. ; Hochstrasser, Megan L. ; Langlois, Christine R. ; Serio, Tricia R. / Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing. In: eLife. 2014 ; Vol. 3.
@article{e6f57d41cbf247dca94ac8faf8ed61c6,
title = "Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing",
abstract = "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.",
keywords = "amyloid, cell biology, chaperone, prion, protein misfolding, S. cerevisiae",
author = "Klaips, {Courtney L.} and Hochstrasser, {Megan L.} and Langlois, {Christine R.} and Serio, {Tricia R}",
year = "2014",
doi = "10.7554/eLife.04288",
language = "English (US)",
volume = "3",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing

AU - Klaips, Courtney L.

AU - Hochstrasser, Megan L.

AU - Langlois, Christine R.

AU - Serio, Tricia R

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - amyloid

KW - cell biology

KW - chaperone

KW - prion

KW - protein misfolding

KW - S. cerevisiae

UR - http://www.scopus.com/inward/record.url?scp=85005847591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85005847591&partnerID=8YFLogxK

U2 - 10.7554/eLife.04288

DO - 10.7554/eLife.04288

M3 - Article

VL - 3

JO - eLife

JF - eLife

SN - 2050-084X

ER -