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

eLife

Luna O Gonzalez¹  Yu-Shan Lin²  Angela M Phillips³  Jesse D Bloom⁴  Vincent L Butty⁵  Matthew D Shoulders⁶  Michael B Doud⁶ 

[1] Department of Genome Sciences, University of Washington, Seattle, United States;BioMicro Center, Massachusetts Institute of Technology, Cambridge, United States;Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States;Department of Chemistry, Tufts University, Medford, United States;Department of Mathematics, Massachusetts Institute of Technology, Cambridge, United States;Fred Hutchinson Cancer Research Center, Seattle, United States;

关键词: influenza;    evolution;    proteostasis;    protein folding;    unfolded protein response;    membrane protein;   

DOI  :  10.7554/eLife.38795

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown