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Nat Commun. 2019 Dec 4;10(1):5518. doi: 10.1038/s41467-019-13520-8.

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

Author information

1
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
2
Unit 17 "Influenza and other Respiratory Viruses", Robert Koch Institut, Seestrase 10, 13353, Berlin, Germany.
3
Structural Interactomics, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
4
Division of Theoretical Systems Biology, German Cancer Research Center, 69120, Heidelberg, Germany.
5
Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
6
Department of Biology, Southern University of Science and Technology, Xuanyuan Road 1088, 518055, Shenzhen, China.
7
Freie Universität Berlin, Department of Biology, Chemistry, Pharmacy Institute of Chemistry and Biochemistry, Thielallee 63, 14195, Berlin, Germany.
8
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125, Berlin, Germany. matthias.selbach@mdc-berlin.de.
9
Charité Universitätsmedizin Berlin, 10117, Berlin, Germany. matthias.selbach@mdc-berlin.de.

Abstract

Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain and observe striking differences in viral protein synthesis. Most importantly, the matrix protein M1 is inefficiently produced by the bird-adapted strain. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Strain-specific M segment splicing is controlled by the 3' splice site and functionally important for permissive infection. In silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, we identify M segment RNA splicing as a viral host range determinant.

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