Na+/K+-ATPase β1 subunit interacts with M2 proteins of influenza A and B viruses and affects the virus replication

Interplay between the host and influenza virus has a pivotal role for the outcome of infection. The matrix proteins M2/BM2 from influenza (A and B) viruses are small type III integral membrane proteins with a single transmembrane domain, a short amino-terminal ectodomain and a long carboxy-terminal cytoplasmic domain. They function as proton channels, mainly forming a membrane-spanning pore through the transmembrane domain tetramer, and are essential for virus assembly and release of the viral genetic materials in the endosomal fusion process. However, little is known about the host factors which interact with M2/BM2 proteins and the functions of the long cytoplasmic domain are currently unknown. Starting with yeast two-hybrid screening and applying a series of experiments we identified that the beta 1 subunit of the host Na+/K+-ATPase beta 1 subunit (ATP1B1) interacts with the cytoplasmic domain of both the M2 and BM2 proteins. A stable ATP1B1 knockdown MDCK cell line was established and we showed that the ATP1B1 knockdown suppressed influenza virus A/WSN/33 replication, implying that the interaction is crucial for influenza virus replication in the host cell. We propose that influenza virus M2/BM2 cytoplasmic domain has an important role in the virus-host interplay and facilitates virus replication.