the ras–pi3k signaling pathway is involved in clathrin-independent endocytosis and the internalization of influenza virusesras-pi3k信号通路参与clathrin-independent内吞作用和流感病毒的内化.pdfVIP

The Ras–PI3K Signaling Pathway Is Involved in Clathrin- Independent Endocytosis and the Internalization of Influenza Viruses 1 1 2 3 3 2 Yoichiro Fujioka , Masumi Tsuda , Tomoe Hattori , Junko Sasaki , Takehiko Sasaki , Tadaaki Miyazaki , Yusuke Ohba1* 1 Laboratory of Pathophysiology and Signal Transduction, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 2 Department of Bioresources, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan, 3 Division of Microbiology, Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan 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. Methodology/Principal Findings: 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/Significance: Tak