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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/38795 |
| _version_ | 1811181119513559040 |
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| author | Angela M Phillips Michael B Doud Luna O Gonzalez Vincent L Butty Yu-Shan Lin Jesse D Bloom Matthew D Shoulders |
| author_facet | Angela M Phillips Michael B Doud Luna O Gonzalez Vincent L Butty Yu-Shan Lin Jesse D Bloom Matthew D Shoulders |
| author_sort | Angela M Phillips |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:14:14Z |
| format | Article |
| id | doaj.art-bde65080ca6046dca52b4266f86786eb |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:14:14Z |
| publishDate | 2018-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-bde65080ca6046dca52b4266f86786eb2022-12-22T04:32:25ZengeLife Sciences Publications LtdeLife2050-084X2018-09-01710.7554/eLife.38795Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutininAngela M Phillips0https://orcid.org/0000-0002-9806-7574Michael B Doud1https://orcid.org/0000-0002-8172-6342Luna O Gonzalez2Vincent L Butty3Yu-Shan Lin4https://orcid.org/0000-0001-6460-2877Jesse D Bloom5https://orcid.org/0000-0003-1267-3408Matthew D Shoulders6https://orcid.org/0000-0002-6511-3431Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United StatesFred Hutchinson Cancer Research Center, Seattle, United States; Department of Genome Sciences, University of Washington, Seattle, United StatesDepartment of Mathematics, Massachusetts Institute of Technology, Cambridge, United StatesBioMicro Center, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Chemistry, Tufts University, Medford, United StatesFred Hutchinson Cancer Research Center, Seattle, United States; Department of Genome Sciences, University of Washington, Seattle, United StatesDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, United StatesWe 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.https://elifesciences.org/articles/38795influenzaevolutionproteostasisprotein foldingunfolded protein responsemembrane protein |
| spellingShingle | Angela M Phillips Michael B Doud Luna O Gonzalez Vincent L Butty Yu-Shan Lin Jesse D Bloom Matthew D Shoulders Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin eLife influenza evolution proteostasis protein folding unfolded protein response membrane protein |
| 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 | influenza evolution proteostasis protein folding unfolded protein response membrane protein |
| url | https://elifesciences.org/articles/38795 |
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