title: The Ras-PI3K signaling pathway is involved in clathrin-independent endocytosis and the internalization of influenza viruses.
abstract: BACKGROUND
  Influenza virus infection causes highly contagious, severe respiratory disorders and gives rise to thousands of deaths every year; however, the efficacy of currently approved defense strategies, including vaccines and neuraminidase inhibitors, is limited because the virus frequently acquires resistance via antigen drift and reassortment. It is therefore important to establish a novel, effective therapeutic strategy that is effective irrespective of viral subtype.
  
  
  RESULTS
  Here, we identify the Ras-phosphoinositide 3-kinase (PI3K) signaling pathway as a host-cell regulatory mechanism for influenza virus entry. The binding of Ras to PI3K is specifically involved in clathrin-independent endocytosis, endosomal maturation, and intracellular transport of viruses, which result in decreased infectious efficacy of different subtypes of influenza viruses in cells lacking the Ras-PI3K interaction. Moreover, influenza virus infection indeed triggered Ras activation and subsequent PI3K activation in early endosomes.
  
  
  CONCLUSIONS
  Taken together, these results demonstrate that the Ras-PI3K signaling axis acts as a host-oriented mechanism for viral internalization. Given that virus incorporation is a process conserved among virus subtypes and species, this signaling pathway may provide a target for potent, well-tolerated prophylactics and therapeutics against a broad range of viruses.
authors.affiliation: Laboratory of Pathophysiology and Signal Transduction, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.forename: Tomoe
authors.initials: T
authors.lastname: Hattori
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
mesh_terms: D002460:Cell Line; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D009975:Orthomyxoviridae / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D053586:Virus Internalization; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins