Fig. 6

Model of copper-mediated regulation of the influenza virus life cycle. Extracellular copper [Cu²⁺] shares topological space with virion binding to host cell, and viral entry steps within the endosome. CTR1 imports extracellular copper to the cytoplasm. Intracellular copper [Cu¹⁺] is associated with the ATOX1 chaperone and other metalloproteins. From there, copper is actively transported into the secretory pathway by ATP7A. ATP7A plays a role determining copper concentration in the cytosol and in ER, Golgi, and other membrane bound compartments, where the viral glycoproteins HA and NA (o) are synthesized and mature. New viral RNA are synthesized in the nucleus, where ATOX1 may transport intracellular [Cu¹⁺]. In complex with matrix proteins (M1 and M2, ☐), genomic viral RNA progeny are exported from the nucleus to associate with M1, M2, HA, NA and other proteins to assemble budding virions at the plasma membrane, a site that is topologically in the cytosol