The ubiquitination landscape of the influenza A virus polymerase

Franziska Günl, Tim Krischuns, Julian A. Schreiber, Lea Henschel, Marius Wahrenburg, Hannes C. A. Drexler, Sebastian A. Leidel, Vlad Cojocaru, Guiscard Seebohm, Alexander Mellmann, Martin Schwemmle, Stephan Ludwig and Linda Brunotte ()
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Franziska Günl: University of Muenster
Tim Krischuns: University of Muenster
Julian A. Schreiber: University of Muenster
Lea Henschel: University of Muenster
Marius Wahrenburg: University of Muenster
Hannes C. A. Drexler: Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine
Sebastian A. Leidel: University of Bern
Vlad Cojocaru: Max Planck Institute for Molecular Biomedicine
Guiscard Seebohm: University Hospital Muenster
Alexander Mellmann: University of Muenster
Martin Schwemmle: University Medical Center Freiburg
Stephan Ludwig: University of Muenster
Linda Brunotte: University of Muenster

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication.

Date: 2023
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DOI: 10.1038/s41467-023-36389-0

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