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Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane

BACKGROUND: Misfolded proteins are generally recognised by cellular quality control machinery, which typically results in their ubiquitination and degradation. For soluble cytoplasmic proteins, degradation is mediated by the proteasome. Membrane proteins that fail to fold correctly are subject to ER...

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Detalles Bibliográficos
Autores principales: Lewis, Michael J., Pelham, Hugh R. B.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659772/
https://www.ncbi.nlm.nih.gov/pubmed/19337370
http://dx.doi.org/10.1371/journal.pone.0005038
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author Lewis, Michael J.
Pelham, Hugh R. B.
author_facet Lewis, Michael J.
Pelham, Hugh R. B.
author_sort Lewis, Michael J.
collection PubMed
description BACKGROUND: Misfolded proteins are generally recognised by cellular quality control machinery, which typically results in their ubiquitination and degradation. For soluble cytoplasmic proteins, degradation is mediated by the proteasome. Membrane proteins that fail to fold correctly are subject to ER associated degradation (ERAD), which involves their extraction from the membrane and subsequent proteasome-dependent destruction. Proteins with abnormal transmembrane domains can also be recognised in the Golgi or endosomal system and targeted for destruction in the vacuole/lysosome. It is much less clear what happens to membrane proteins that reach their destination, such as the cell surface, and then suffer damage. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the ability of yeast cells to degrade membrane proteins to which temperature-sensitive cytoplasmic alleles of the Ura3 protein or of phage lambda repressor have been fused. In soluble form, these proteins are rapidly degraded upon temperature shift, in part due to the action of the Doa10 and San1 ubiquitin ligases and the proteasome. When tethered to the ER protein Use1, they are also degraded. However, when tethered to a plasma membrane protein such as Sso1 they escape degradation, either in the vacuole or by the proteasome. CONCLUSIONS/SIGNIFICANCE: Membrane proteins with a misfolded cytoplasmic domain appear not to be efficiently recognised and degraded once they have escaped the ER, even though their defective domains are exposed to the cytoplasm and potentially to cytoplasmic quality controls. Membrane tethering may provide a way to reduce degradation of unstable proteins.
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spelling pubmed-26597722009-04-01 Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane Lewis, Michael J. Pelham, Hugh R. B. PLoS One Research Article BACKGROUND: Misfolded proteins are generally recognised by cellular quality control machinery, which typically results in their ubiquitination and degradation. For soluble cytoplasmic proteins, degradation is mediated by the proteasome. Membrane proteins that fail to fold correctly are subject to ER associated degradation (ERAD), which involves their extraction from the membrane and subsequent proteasome-dependent destruction. Proteins with abnormal transmembrane domains can also be recognised in the Golgi or endosomal system and targeted for destruction in the vacuole/lysosome. It is much less clear what happens to membrane proteins that reach their destination, such as the cell surface, and then suffer damage. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the ability of yeast cells to degrade membrane proteins to which temperature-sensitive cytoplasmic alleles of the Ura3 protein or of phage lambda repressor have been fused. In soluble form, these proteins are rapidly degraded upon temperature shift, in part due to the action of the Doa10 and San1 ubiquitin ligases and the proteasome. When tethered to the ER protein Use1, they are also degraded. However, when tethered to a plasma membrane protein such as Sso1 they escape degradation, either in the vacuole or by the proteasome. CONCLUSIONS/SIGNIFICANCE: Membrane proteins with a misfolded cytoplasmic domain appear not to be efficiently recognised and degraded once they have escaped the ER, even though their defective domains are exposed to the cytoplasm and potentially to cytoplasmic quality controls. Membrane tethering may provide a way to reduce degradation of unstable proteins. Public Library of Science 2009-04-01 /pmc/articles/PMC2659772/ /pubmed/19337370 http://dx.doi.org/10.1371/journal.pone.0005038 Text en Lewis et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lewis, Michael J.
Pelham, Hugh R. B.
Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title_full Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title_fullStr Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title_full_unstemmed Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title_short Inefficient Quality Control of Thermosensitive Proteins on the Plasma Membrane
title_sort inefficient quality control of thermosensitive proteins on the plasma membrane
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659772/
https://www.ncbi.nlm.nih.gov/pubmed/19337370
http://dx.doi.org/10.1371/journal.pone.0005038
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