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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...

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Autores principales: Phillips, Angela M, Doud, Michael B, Gonzalez, Luna O, Butty, Vincent L, Lin, Yu-Shan, Bloom, Jesse D, Shoulders, Matthew D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
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.
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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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