Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin
Name
elife-38795-v2.pdf
Description
Published version
Size
4.13 MB
Format
Adobe PDF
Checksum (MD5)
58ee92564d976f48e22b00bd1ad2c2e9
Author(s)
Phillips, Angela Marie
Gonzalez, Luna O.
Butty, Vincent L G
Shoulders, Matthew D.
Date Issued
September 2018
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Phillips, Angela M. et al. “Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin.” eLife 7 (2018): e38795 © 2018 The Author(s)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Mathematics
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/ELIFE.38795
