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 integrat...

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Published ineLife Vol. 7
Main Authors Phillips, Angela M, Doud, Michael B, Gonzalez, Luna O, Butty, Vincent L, Lin, Yu-Shan, Bloom, Jesse D, Shoulders, Matthew D
Format Journal Article
LanguageEnglish
Published England eLife Science Publications, Ltd 06.09.2018
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects
Amino Acid Sequence
Amino acids
Antibodies
Biochemistry and Chemical Biology
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Stress - genetics
Evolution
Evolutionary Biology
Fever
Gene Expression Profiling
Genetic aspects
Haplotypes
HEK293 Cells
Hemagglutinin Glycoproteins, Influenza Virus - genetics
Hemagglutinin Glycoproteins, Influenza Virus - metabolism
Hemagglutinins
Humans
Immunological tolerance
Influenza
Lectins
membrane protein
Membrane proteins
Mutation
Protein folding
Proteins
Proteostasis
Quality control
Regression analysis
Secretory Pathway - genetics
Temperature
Temperature tolerance
Tetracyclines
unfolded protein response
Unfolded Protein Response - genetics
United States > US
Massachusetts
influenza
unfolded protein response
evolutionary biology
chemical biology
biochemistry
membrane protein
protein folding
evolution
proteostasis
human
virus
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Abstract 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.
AbstractList 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.
Audience Academic
Author Phillips, Angela M
Bloom, Jesse D
Doud, Michael B
Gonzalez, Luna O
Lin, Yu-Shan
Butty, Vincent L
Shoulders, Matthew D
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  givenname: Michael B
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2018, Phillips et al. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2018, Phillips et al 2018 Phillips et al
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Keywords influenza
unfolded protein response
evolutionary biology
chemical biology
biochemistry
membrane protein
protein folding
evolution
proteostasis
human
virus
Language English
License 2018, Phillips et al.
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Snippet We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway...
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SubjectTerms Amino Acid Sequence
Amino acids
Antibodies
Biochemistry and Chemical Biology
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Stress - genetics
Evolution
Evolutionary Biology
Fever
Gene Expression Profiling
Genetic aspects
Haplotypes
HEK293 Cells
Hemagglutinin Glycoproteins, Influenza Virus - genetics
Hemagglutinin Glycoproteins, Influenza Virus - metabolism
Hemagglutinins
Humans
Immunological tolerance
Influenza
Lectins
membrane protein
Membrane proteins
Mutation
Protein folding
Proteins
Proteostasis
Quality control
Regression analysis
Secretory Pathway - genetics
Temperature
Temperature tolerance
Tetracyclines
unfolded protein response
Unfolded Protein Response - genetics
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Title Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin
URI https://www.ncbi.nlm.nih.gov/pubmed/30188321
https://www.proquest.com/docview/2127571939
https://pubmed.ncbi.nlm.nih.gov/PMC6172027
https://doaj.org/article/bde65080ca6046dca52b4266f86786eb
Volume 7
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