Role of influenza A virus matrix protein 1-interacting proteins in vesicle-mediated transport and lipid droplet functional regulation

• Applicant: Dr. Yvonne Börgeling
• Subject Area: Virology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497277245

Annual influenza epidemics as well as recurrent pandemics impressively highlight that influenza A viruses (IAV) still represent a major health threat worldwide. At present, our antiviral arsenal to fight these pathogens is quite limited due to the rapid development of resistance to available drugs invariably targeting viral proteins. Consequently, development of novel strategies for antiviral intervention, which present alternative mechanisms of action, is urgently needed. Due to their small genomes, IAV replication is largely dependent on the cellular machinery and these virus-host interfaces may be suited as targets of novel antiviral approaches.The highly conserved IAV matrix (M1) protein is a master regulator of the virus life cycle, controlling virus replication at multiple stages, including uncoating, RNP transport, and budding. Its multi-functionality qualifies M1 as a promising target for combating influenza, as it offers the opportunity to block the infection process at different stages. Clearly, the various functions of M1 must be highly regulated in a spatio-temporal manner to ensure efficient progression of viral replication. Here, the control of intracellular M1 transport is of central importance. We hypothesize that these regulatory interventions are mediated by specific interactions with particular host proteins at specific cellular compartments. Intriguingly, intracellular transport mechanisms of M1 are still largely unclear. Recently, we identified a putative tyrosine-based sorting motif in M1 that is highly conserved among IAV strains and subtypes, suggesting a role of this motif in intracellular M1 trafficking. Furthermore, bioinformatic analyses of the M1 interactome revealed several proteins involved in vesicle-mediated transport. Of these, Rab18 and VAT-1 are functionally related to lipid droplets (LDs). LDs have emerged as critical for virus replication and assembly, acting as hubs that integrate metabolic and inflammatory processes. LDs are also sequestration sites for proteins that have roles outside LD function. Identification of LD-associated proteins as M1 interactors suggests a role for LDs in M1 sequestration or indicates that M1 is involved in the control of LD function.We aim to investigate whether the tyrosine-based sorting motif in M1 as well as the presence of specific M1-binding proteins at distinct cellular compartments recruit M1 to specific target sites to fulfil or mitigate its functions. Characterization of the role of these M1-host interactions constitutes another step forward to a better understanding of intracellular trafficking of viral proteins and helps to identify new targets for antiviral interventions. 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