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1.
Elife ; 72018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30188321

RESUMO

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.


Assuntos
Retículo Endoplasmático/metabolismo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Mutação , Proteostase , Temperatura , Sequência de Aminoácidos , Estresse do Retículo Endoplasmático/genética , Perfilação da Expressão Gênica , Células HEK293 , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Via Secretória/genética , Resposta a Proteínas não Dobradas/genética
2.
Elife ; 62017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28949290

RESUMO

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host-pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.


Assuntos
Aptidão Genética , Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H3N2/genética , Mutação , Proteostase , Proteínas Virais/genética , Animais , Cães , Evolução Molecular , Vírus da Influenza A Subtipo H3N2/fisiologia , Células Madin Darby de Rim Canino , Seleção Genética , Proteínas Virais/metabolismo
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