Regulation of the influenza A virus polymerase activity by post-translational ubiquitin-modification
Final Report Abstract
Influenza A viruses (IAV) are triggers of seasonal, sometimes severe respiratory diseases that particularly affect young children and elderly people or individuals with immune insufficiency. During infection, the virus is dependent on the resources of the host cell to enable replication of its own genetic material and the production of new virus particles. Many of the necessary interactions of IAV with cellular processes have not yet been fully elucidated. This project focused on the question whether the activity of the viral polymerase of IAV can be regulated by posttranslational modifications, such as ubiquitinylation (UB), generated by cellular E3 ligases. Using a special method for the purification of UB-modified proteins, we were able to describe for the first time exactly which lysines in the proteins of the IAV polymerase are modified by ubiquitin. By functional analysis, we were also able to show that some of these modifications actually had a direct effect on viral mRNA transcription while others affected genome replication. Especially the modification of the lysine at position 578 within the thumb domain of the PB1 protein showed an interesting phenotype. Through functional studies and in silico analyses, we were able to reveal that the UB status at this position controls the dynamic structural changes required for successful genome replication. Through these results, we were able to show for the first time that IAV utilize the ubiquitin system of infected cells to coordinate their own replication. Potentially, the findings of our study can be used to develop new antiviral drugs that aim to control post-translational modifications of viral proteins, thereby blocking viral replication.
Publications
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Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells. Frontiers in Immunology, 9.
Krischuns, Tim; Günl, Franziska; Henschel, Lea; Binder, Marco; Willemsen, Joschka; Schloer, Sebastian; Rescher, Ursula; Gerlt, Vanessa; Zimmer, Gert; Nordhoff, Carolin; Ludwig, Stephan & Brunotte, Linda
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„Detecting Ubiquitination of the influenza virus NS1 protein.“ (3rd Symposium of Infection Biology, Münster 2019; 29th Annual meeting of the Society of virology, Düsseldorf 2019)
Günl F.,Krischuns T., Janowski J., Leidel. S., Drexler., Ludwig S. & Brunotte L.
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„The role of site-specific ubiquitination of the influenza A virus polymerase” (Schau ins Land-Retreat des Instituts für Virologie der Universität Freiburg, 2019)
Franziska Günl
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„The role of site-specific ubiquitination of the influenza A virus polymerase” (Retreat des Instituts für Virologie Münster, 2020)
Franziska Günl
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„The role of site-specific ubiquitination of the influenza A virus polymerase” (Viruses 2020 - Novel Concepts in Virology, Barcelona 2020)
Günl F., Krischuns T., Henschel L., Wahrenburg M., Drexler H. C. A., Leidel S. A., Schwemmle M., Seebohm G., Ludwig S. & Brunotte L.
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Shooting at a Moving Target—Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development. Vaccines, 9(10), 1052.
Günl, Franziska; Mecate-Zambrano, Angeles; Rehländer, Selina; Hinse, Saskia; Ludwig, Stephan & Brunotte, Linda
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“Exploiting Human Interferon-Alpha Subtypes for Prevention of Inflammation during SARS-CoV-2 Infection in Human Lung Explants” (1st Symposium Inflammation and Imaging, Münster 2021)
Mecate Zambrano A., Kumar S., Hinse S., Günl F., Faist A., Rehländer S., Christersson A., Janowski J., Schughart K., Lecanda A., Wiewrodt R., Wiebe K., Barth P., Schöler H. R., Ludwig S. & Brunotte
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“Site-specific ubiquitination of the influenza A virus polymerase is required to dynamically regulate the replication of the viral genome” (31st Annual meeting of the German Society of Virology, 2022)
Franziska Günl
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The role of site-specific ubiquitination of the influenza A virus polymerase” (30th Annual meeting of the German Society of Virology, 2022)
Franziska Günl
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„The role of site-specific ubiquitination of the influenza A virus polymerase” (Annual conference of the Microbiology Society, 2022, Belfast, UK)
Franziska Günl
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Glycolytic interference blocks influenza A virus propagation by impairing viral polymerase-driven synthesis of genomic vRNA. PLOS Pathogens, 19(7), e1010986.
Kleinehr, Jens; Schöfbänker, Michael; Daniel, Katharina; Günl, Franziska; Mohamed, Fakry Fahmy; Janowski, Josua; Brunotte, Linda; Boergeling, Yvonne; Liebmann, Marie; Behrens, Matthias; Gerdemann, Andrea; Klotz, Luisa; Esselen, Melanie; Humpf, Hans-Ulrich; Ludwig, Stephan & Hrincius, Eike R.
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The ubiquitination landscape of the influenza A virus polymerase. Nature Communications, 14(1).
Günl, Franziska; Krischuns, Tim; Schreiber, Julian A.; Henschel, Lea; Wahrenburg, Marius; Drexler, Hannes C. A.; Leidel, Sebastian A.; Cojocaru, Vlad; Seebohm, Guiscard; Mellmann, Alexander; Schwemmle, Martin; Ludwig, Stephan & Brunotte, Linda
