Impact of cellular protein phosphatase 2A on the regulation of influenza A virus matrix protein (M1) functions in the viral life cycle

• Applicant: Dr. Yvonne Börgeling
• Subject Area: Virology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392415665

Influenza viruses still represent a major health threat world-wide. Our antiviral arsenal to fight these pathogens is currently quite limited due to the rapid development of resistance to currently available drugs. Thus, development of novel strategies for antiviral intervention is urgently needed. The highly conserved influenza virus matrix (M1) protein is a master regulator of the virus life cycle controlling virus replication on several stages such as uncoating, RNP transport and budding. Its multifunctionality qualifies M1 as a promising target for combating influenza, as it provides the opportunity to potentially block infections at various stages. The different functions of this protein are mediated by binding to other viral or cellular proteins which is most likely controlled by posttranslational modifications in a spatiotemporal manner. Phosphorylation/dephosphorylation is a major regulatory switch that directs many cellular processes and we previously identified highly conserved phosphorylation acceptor sites within the M1 protein suggesting a universal role in viral replication. Interestingly, analysis of the M1 interactome unraveled several regulatory subunits of the protein phosphatase 2A (PP2A). Phosphorylation is known to be a dynamic and highly regulated process, but the role of respective phosphatases has not been addressed in the context of influenza virus infections, so far. We hypothesize that M1 might be a direct target of PP2A-mediated dephosphorylation or might recruit the complex to specific viral or cellular targets whose dephosphorylation is needed for efficient viral replication. Therefore, the aim of this study is to identify the different PP2A targets during viral life cycle progression with a major focus on the regulation of M1 function.Identification of M1 functions prone to PP2A-mediated dephosphorylation during the virus life cycle will help to gain important insights in the regulation of viral replication. Further knowledge about the M1-host interplay is key to uncover new leads for pharmaceutical intervention. Blocking cellular activities that are indispensable for virus propagation will ensure interference with replication of a broad range of existing and newly emerging influenza viruses with a high barrier towards generation of resistant variants.

• DFG Programme: Research Grants