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The degradation pathway of a model misfolded protein is determined by aggregation propensity
Protein homeostasis in the secretory pathway is maintained by a hierarchy of quality control checkpoints, including endoplasmic reticulum–associated degradation (ERAD), which leads to the destruction of misfolded proteins in the ER, as well as post-ER proteolysis. Although most aberrant proteins are...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014095/ https://www.ncbi.nlm.nih.gov/pubmed/29688814 http://dx.doi.org/10.1091/mbc.E18-02-0117 |
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author | Sun, Zhihao Brodsky, Jeffrey L. |
author_facet | Sun, Zhihao Brodsky, Jeffrey L. |
author_sort | Sun, Zhihao |
collection | PubMed |
description | Protein homeostasis in the secretory pathway is maintained by a hierarchy of quality control checkpoints, including endoplasmic reticulum–associated degradation (ERAD), which leads to the destruction of misfolded proteins in the ER, as well as post-ER proteolysis. Although most aberrant proteins are degraded by ERAD, some misfolded proteins escape the ER and are degraded instead by lysosomal/vacuolar proteases. To date, it remains unclear how misfolded membrane proteins are selected for these different fates. Here we designed a novel model substrate, SZ*, to investigate how substrate selection is mediated in yeast. We discovered that SZ* is degraded by both the proteasome and vacuolar proteases, the latter of which occurs after ER exit and requires the multivesicular body pathway. By interrogating how various conditions affect the fate of SZ*, we also discovered that heat-shock and substrate overexpression increase ERAD targeting. These conditions also increase substrate aggregation. We next found that aggregation of the membrane-free misfolded domain in SZ* is concentration dependent, and fusion of this misfolded domain to a post-ER quality control substrate instead targets the substrate for ERAD. Our data indicate that a misfolded membrane protein with a higher aggregation propensity is preferentially retained in the ER and targeted for ERAD. |
format | Online Article Text |
id | pubmed-6014095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-60140952018-08-30 The degradation pathway of a model misfolded protein is determined by aggregation propensity Sun, Zhihao Brodsky, Jeffrey L. Mol Biol Cell Articles Protein homeostasis in the secretory pathway is maintained by a hierarchy of quality control checkpoints, including endoplasmic reticulum–associated degradation (ERAD), which leads to the destruction of misfolded proteins in the ER, as well as post-ER proteolysis. Although most aberrant proteins are degraded by ERAD, some misfolded proteins escape the ER and are degraded instead by lysosomal/vacuolar proteases. To date, it remains unclear how misfolded membrane proteins are selected for these different fates. Here we designed a novel model substrate, SZ*, to investigate how substrate selection is mediated in yeast. We discovered that SZ* is degraded by both the proteasome and vacuolar proteases, the latter of which occurs after ER exit and requires the multivesicular body pathway. By interrogating how various conditions affect the fate of SZ*, we also discovered that heat-shock and substrate overexpression increase ERAD targeting. These conditions also increase substrate aggregation. We next found that aggregation of the membrane-free misfolded domain in SZ* is concentration dependent, and fusion of this misfolded domain to a post-ER quality control substrate instead targets the substrate for ERAD. Our data indicate that a misfolded membrane protein with a higher aggregation propensity is preferentially retained in the ER and targeted for ERAD. The American Society for Cell Biology 2018-06-15 /pmc/articles/PMC6014095/ /pubmed/29688814 http://dx.doi.org/10.1091/mbc.E18-02-0117 Text en © 2018 Sun and Brodsky “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0/ This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Sun, Zhihao Brodsky, Jeffrey L. The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title | The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title_full | The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title_fullStr | The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title_full_unstemmed | The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title_short | The degradation pathway of a model misfolded protein is determined by aggregation propensity |
title_sort | degradation pathway of a model misfolded protein is determined by aggregation propensity |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014095/ https://www.ncbi.nlm.nih.gov/pubmed/29688814 http://dx.doi.org/10.1091/mbc.E18-02-0117 |
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