Analysis of novel functions and interaction partners of the influenza A virus PB1-F2 protein
Final Report Abstract
Influenza A viruses (IAV) are worldwide circulating pathogens that cause annual epidemics and occasionally worldwide pandemics, infecting millions of people, therefore, still being a major global public health problem. As IAV strongly depends on the host metabolic and signal transduction machinery for its efficient replication it is of great importance to identify viral pathogenicity factors and understand how they interact with the host cell response. PB1-F2 is such a viral pathogenicity factor, which was shown to have pro-apoptotic functions. Our own preliminary work demonstrated that PB1-F2 interacts with several cellular proteins and potentially has an IFN-antagonistic activity. Therefore we aimed to investigate this IFN-antagonistic activity and characterize the new interaction partners hGBP-3 and CD74 of PB1-F2 we have identified in preliminary studies. Indeed, we were able to verify our hypothesis of PB1-F2 as IFN-antagonist by unraveling an interference of PB1-F2 with the RIG-I/MAVS signaling pathway. Although we could confirm an interaction of PB1-F2 with hGBP-3 we were unable to demonstrate an impact of this interaction on the outcome of viral replication or pathogenicity. Interestingly, we identified a new splice variant of hGBP-3, that we named hGBP-3ΔC, which showed a strong anti-IAV activity. Furthermore, in the process of analyzing the role of the proteasome for the stability of PB1-F2 during viral replication we were able to identify that the proteasome inhibitor PS-341 has antiviral activity and acts by an unexpected induction of innate immune response genes.
Publications
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(2009). Phosphorylation of the influenza A virus protein PB1-F2 by PKC is crucial for apoptosis promoting functions in monocytes. Cellular Microbiology, 11(10), 1502–16
Mitzner, D., Dudek, S. E., Studtrucker, N., Anhlan, D., Mazur, I., Wissing, J., Jänsch, L., Wixler, L., Bruns, K., Sharma, A., Wray, V., Henklein, P., Ludwig, S., & Schubert, U.
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(2010). Monoclonal antibodies against the PB1-F2 protein of H1N1 influenza A virus. Hybridoma, 29(4), 321–6
Nordmann, A., Wixler, L., Ludwig, S., & Wixler, V.
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(2010). The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza A virus and vesicular stomatitis virus propagation by establishing an antiviral state. Journal of Virology, 84(18), 9439–51
Dudek, S. E., Luig, C., Pauli, E.-K., Schubert, U., & Ludwig, S.
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(2011). The influenza virus PB1-F2 protein has interferon antagonistic activity. Biological Chemistry, 392(12), 1135–44
Dudek, S. E., Wixler, L., Nordhoff, C., Nordmann, A., Anhlan, D., Wixler, V., & Ludwig, S.
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(2012). A new splice variant of the human guanylate-binding protein 3 mediates anti-influenza activity through inhibition of viral transcription and replication. The FASEB Journal, 26(3), 1290–1300
Nordmann, A., Wixler, L., Boergeling, Y., Wixler, V., & Ludwig, S.
