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The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

Item Type:Preprint
Title:The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant
Creators Name:Bogdanow, B. and Eichelbaum, K. and Sadewasser, A. and Wang, X. and Husic, I. and Paki, K. and Hergeselle, M. and Vetter, B. and Hou, J. and Chen, W. and Wiebusch, L. and Meyer, I.M. and Wolff, T. and Selbach, M.
Abstract:A century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3′ splice site and functionally important for permissive infection. Independent in silico evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Article Number:438176
Date:8 October 2018
Official Publication:https://doi.org/10.1101/438176

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