title: A Ca(2+)-dependent signalling circuit regulates influenza A virus internalization and infection.
abstract: Various viruses enter host cells via endocytosis, but the molecular mechanisms underlying the specific internalization pathways remain unclear. Here we show that influenza A viruses (IAVs) enter cells via redundant pathways of clathrin-mediated and clathrin-independent endocytosis, with intracellular Ca(2+) having a central role in regulation of both pathways by activating a signalling axis comprising RhoA, Rho-kinase, phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and phospholipase C (PLC). IAV infection induces oscillations in the cytosolic Ca(2+) concentration of host cells, the prevention of which markedly attenuates virus internalization and infection. The small GTPase RhoA is found both to function downstream of the virus-induced Ca(2+) response and itself to induce Ca(2+) oscillations in a manner dependent on Rho-kinase and subsequent PIP5K-PLC signalling. This signalling circuit regulates both clathrin-mediated and clathrin-independent endocytosis during virus infection and seems to constitute a key mechanism for regulation of IAV internalization and infection.
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15W7, Sapporo 060-8638, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, N15W7, Sapporo 060-8638, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15W7, Sapporo 060-8638, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Nanbo
authors.affiliation: Department of Bioresources, Hokkaido University Research Centre for Zoonosis Control, N20W10, Sapporo 060-0020, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543 Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Department of Medical Biology, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543 Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: 1] Department of Bioresources, Hokkaido University Research Centre for Zoonosis Control, N20W10, Sapporo 060-0020, Japan [2].
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15W7, Sapporo 060-8638, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D004285:Dogs; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D051379:Mice; D054801:Phosphoinositide Phospholipase C; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D054801:Phosphoinositide Phospholipase C; D020742:rhoA GTP-Binding Protein; D002118:Calcium