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Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control

BACKGROUND: Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain...

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Autores principales: Kawaguchi, Shinichi, Hsu, Chia-Ling, Ng, Davis T. W.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991357/
https://www.ncbi.nlm.nih.gov/pubmed/21151492
http://dx.doi.org/10.1371/journal.pone.0015532
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author Kawaguchi, Shinichi
Hsu, Chia-Ling
Ng, Davis T. W.
author_facet Kawaguchi, Shinichi
Hsu, Chia-Ling
Ng, Davis T. W.
author_sort Kawaguchi, Shinichi
collection PubMed
description BACKGROUND: Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain unclear. While some proteins are retained statically, the classical model substrate CPY* is found in COPII transport vesicles, suggesting a retrieval mechanism for retention. However, its management can be even more dynamic. If ERAD is saturated under stress, excess CPY* traffics to the vacuole for degradation. These observations suggest that misfolded proteins might display different signals for their management. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the existence of a functional ER exit signal in the pro-domain of CPY*. Compromising its integrity causes ER retention through exclusion from COPII vesicles. The signal co-exists with other signals used for retention and degradation. Physiologically, the export signal is important for stress tolerance. Disabling it converts a benign protein into one that is intrinsically cytotoxic. CONCLUSIONS/SIGNIFICANCE: These data reveal the remarkable interplay between opposing signals embedded within ERAD substrate molecules and the mechanisms that decipher them. Our findings demonstrate the diversity of mechanisms deployed for protein quality control and maintenance of protein homeostasis.
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spelling pubmed-29913572010-12-10 Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control Kawaguchi, Shinichi Hsu, Chia-Ling Ng, Davis T. W. PLoS One Research Article BACKGROUND: Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain unclear. While some proteins are retained statically, the classical model substrate CPY* is found in COPII transport vesicles, suggesting a retrieval mechanism for retention. However, its management can be even more dynamic. If ERAD is saturated under stress, excess CPY* traffics to the vacuole for degradation. These observations suggest that misfolded proteins might display different signals for their management. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the existence of a functional ER exit signal in the pro-domain of CPY*. Compromising its integrity causes ER retention through exclusion from COPII vesicles. The signal co-exists with other signals used for retention and degradation. Physiologically, the export signal is important for stress tolerance. Disabling it converts a benign protein into one that is intrinsically cytotoxic. CONCLUSIONS/SIGNIFICANCE: These data reveal the remarkable interplay between opposing signals embedded within ERAD substrate molecules and the mechanisms that decipher them. Our findings demonstrate the diversity of mechanisms deployed for protein quality control and maintenance of protein homeostasis. Public Library of Science 2010-11-24 /pmc/articles/PMC2991357/ /pubmed/21151492 http://dx.doi.org/10.1371/journal.pone.0015532 Text en Kawaguchi 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
Kawaguchi, Shinichi
Hsu, Chia-Ling
Ng, Davis T. W.
Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title_full Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title_fullStr Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title_full_unstemmed Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title_short Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control
title_sort interplay of substrate retention and export signals in endoplasmic reticulum quality control
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991357/
https://www.ncbi.nlm.nih.gov/pubmed/21151492
http://dx.doi.org/10.1371/journal.pone.0015532
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