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Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin
We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemaggluttinin (HA), a viral membrane protein that folds in the host’s ER via a complex pathway. By integrating c...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172027/ https://www.ncbi.nlm.nih.gov/pubmed/30188321 http://dx.doi.org/10.7554/eLife.38795 |
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author | Phillips, Angela M Doud, Michael B Gonzalez, Luna O Butty, Vincent L Lin, Yu-Shan Bloom, Jesse D Shoulders, Matthew D |
author_facet | Phillips, Angela M Doud, Michael B Gonzalez, Luna O Butty, Vincent L Lin, Yu-Shan Bloom, Jesse D Shoulders, Matthew D |
author_sort | Phillips, Angela M |
collection | PubMed |
description | We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemaggluttinin (HA), a viral membrane protein that folds in the host’s ER via a complex pathway. By integrating chemical methods to modulate ER proteostasis with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER proteostasis factors broadly enhances HA mutational tolerance across diverse structural elements. Remarkably, this proteostasis network-enhanced mutational tolerance occurs at the same sites where mutational tolerance is most reduced by propagation at fever-like temperature. These findings have important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to evade antibodies while maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that ER proteostasis mechanisms define the mutational tolerance and, therefore, the evolution of secretory pathway proteins. |
format | Online Article Text |
id | pubmed-6172027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-61720272018-10-10 Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin Phillips, Angela M Doud, Michael B Gonzalez, Luna O Butty, Vincent L Lin, Yu-Shan Bloom, Jesse D Shoulders, Matthew D eLife Biochemistry and Chemical Biology We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemaggluttinin (HA), a viral membrane protein that folds in the host’s ER via a complex pathway. By integrating chemical methods to modulate ER proteostasis with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER proteostasis factors broadly enhances HA mutational tolerance across diverse structural elements. Remarkably, this proteostasis network-enhanced mutational tolerance occurs at the same sites where mutational tolerance is most reduced by propagation at fever-like temperature. These findings have important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to evade antibodies while maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that ER proteostasis mechanisms define the mutational tolerance and, therefore, the evolution of secretory pathway proteins. eLife Sciences Publications, Ltd 2018-09-06 /pmc/articles/PMC6172027/ /pubmed/30188321 http://dx.doi.org/10.7554/eLife.38795 Text en © 2018, Phillips et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Phillips, Angela M Doud, Michael B Gonzalez, Luna O Butty, Vincent L Lin, Yu-Shan Bloom, Jesse D Shoulders, Matthew D Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title | Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title_full | Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title_fullStr | Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title_full_unstemmed | Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title_short | Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
title_sort | enhanced er proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172027/ https://www.ncbi.nlm.nih.gov/pubmed/30188321 http://dx.doi.org/10.7554/eLife.38795 |
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