Transient Activation of the PI3K-AKT Pathway by Hepatitis C Virus to Enhance Viral Entry

• Published in: The Journal of biological chemistry 2012-12, Vol.287 (50), p.41922-41930
• Main Authors: Liu, Zhe, Tian, Yongjun, Machida, Keigo, Lai, Michael M.C., Luo, Guangxiang, Foung, Steven K.H., Ou, Jing-hsiung James
• Format: Article
• Language: English
• Subjects: Akt; AKT Activation; Cell Line; Enzyme Activation - drug effects; Enzyme Activation - genetics; Enzyme Activation - radiation effects; HCV Co-receptors; HCV E2 Protein; HCV Entry; Hepacivirus - physiology; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C Virus; Humans; Microbiology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PI 3-Kinase (PI3K); Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Signal Transduction; Tetraspanin 28 - genetics; Tetraspanin 28 - metabolism; Ultraviolet Rays; Viral Envelope Proteins - genetics; Viral Envelope Proteins - metabolism; Virus Entry; Virus Internalization; Virus Replication - drug effects; Virus Replication - radiation effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.414789

The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Here we report that hepatitis C virus (HCV) transiently activates the PI3K-AKT pathway. This activation was observed as early as 15 min postinfection, peaked by 30 min, and became undetectable at 24 h postinfection. The activation of AKT could also be mediated by UV-inactivated HCV, HCV pseudoparticle, and the ectodomain of the HCV E2 envelope protein. Because antibodies directed against CD81 and claudin-1, but not antibodies directed against scavenger receptor class B type I or occludin, could also activate AKT, the interaction between HCV E2 and its two co-receptors CD81 and claudin-1 probably triggered the activation of AKT. This activation of AKT by HCV was important for HCV infectivity, because the silencing of AKT by siRNA or the treatment of cells with its inhibitors or with the inhibitor of its upstream regulator PI3K significantly inhibited HCV infection, whereas the expression of constitutively active AKT enhanced HCV infection. The PI3K-AKT pathway is probably involved in HCV entry, because the inhibition of this pathway could inhibit the entry of HCV pseudoparticle but not the VSV pseudoparticle into cells. Furthermore, the treatment of cells with the AKT inhibitor AKT-V prior to HCV infection inhibited HCV infection, whereas the treatment after HCV infection had no obvious effect. Taken together, our studies indicated that HCV transiently activates the PI3K-AKT pathway to facilitate its entry. These results provide important information for understanding HCV replication and pathogenesis and raised the possibility of targeting this cellular pathway to treat HCV patients. Background: The PI3K-AKT pathway is an important signaling pathway that may be affected by viral infections. Results: HCV transiently activates AKT during the early stage of viral infection. The suppression of the PI3K-AKT pathway inhibits HCV entry. Conclusion: HCV transiently activates PI3K-AKT to enhance its entry into the host cell. Significance: The studies provide important information for understanding HCV-host interactions.