Fig 13. Proposed model of ATP1A1-dependent macropinocytic entry of RSV.

On exposure to respiratory epithelial cells, RSV triggers the activation and clustering of ATP1A1 in the plasma membrane through an unknown mechanism. ATP1A1 then signals via phosphorylated Src-kinase and transactivates EGFR by its phosphorylation at Tyr845. Upon activation, EGFR signaling causes cytoskeletal rearrangement resulting in plasma membrane ruffling and formation of membrane extensions (reported previously [31, 33, 34]) that engulf fluid and RSV into macropinosomes. Note that RSV is taken up into the macropinosome in its enveloped state suggesting that it does not fuse at the cell surface; fusion and release of the nucleocapsid likely occurs within the internalized macropinosome.