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Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin

Authors :
Angela M Phillips
Michael B Doud
Luna O Gonzalez
Vincent L Butty
Yu-Shan Lin
Jesse D Bloom
Matthew D Shoulders
Source :
eLife, Vol 7 (2018)
Publication Year :
2018
Publisher :
eLife Sciences Publications Ltd, 2018.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
7
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.bde65080ca6046dca52b4266f86786eb
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.38795