tetano
Editor, Senior Moderator
Elife. 2018 Sep 6;7. pii: e38795. doi: 10.7554/eLife.38795. [Epub ahead of print]
[h=1]Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin.[/h] Phillips AM[SUP]1[/SUP], Doud MB[SUP]2[/SUP], Gonzalez LO[SUP]3[/SUP], Butty VL[SUP]4[/SUP], Lin YS[SUP]5[/SUP], Bloom JD[SUP]2[/SUP], Shoulders MD[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Herein, we systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemagluttinin (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.
[h=4]KEYWORDS:[/h] biochemistry; chemical biology; evolutionary biology; human; viruses
PMID: 30188321 DOI: 10.7554/eLife.38795
Free full text
[h=1]Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin.[/h] Phillips AM[SUP]1[/SUP], Doud MB[SUP]2[/SUP], Gonzalez LO[SUP]3[/SUP], Butty VL[SUP]4[/SUP], Lin YS[SUP]5[/SUP], Bloom JD[SUP]2[/SUP], Shoulders MD[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Herein, we systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemagluttinin (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.
[h=4]KEYWORDS:[/h] biochemistry; chemical biology; evolutionary biology; human; viruses
PMID: 30188321 DOI: 10.7554/eLife.38795
Free full text