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

University of Southern California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2012; 287(50). DOI: 10.1074/jbc.M112.414789
Source: PubMed


The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Here we report that HCV transiently activates the PI3K-AKT pathway. This activation was observed as early as 15 minutes post-infection, peaked by 30 minutes, and became undetectable at 24 hours post-infection. The activation of AKT could also be mediated by UV-inactivated HCV, HCV pseudoparticle (HCVpp) and the ectodomain of the HCV E2 envelope protein. Since antibodies directed against CD81 and claudin-1, but not antibodies directed against SR-BI or occludin, could also activate AKT, the interaction between HCV E2 and its two co-receptors CD81 and claudin-1 likely triggered the activation of AKT. This activation of AKT by HCV was important for HCV infectivity, as 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 likely involved in HCV entry, as the inhibition of this pathway could inhibit the entry of HCVpp but not the VSV pseudoparticle (VSVpp) 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.

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    • ". The activation of p21-activated kinase 1 (PAK1) by p70 S6 kinase during HCV infection was proposed to contribute to the PI3K-mediated regulation of HCV infection [31]. Activation of the PI3K–Akt pathway also required interactions between HCV E2 protein and the CD81–CLDN1 receptor complex [30]. The specific roles of the PI3K–Akt pathway in HCV entry, and the functional relevance in hepatocytes, remain unclear. "
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    • "Thus, it is believed that EGFR promotes CD81-CLDN1 complex formation by inducing CD81 diffusion through HRas activation and facilitates CD81-CLDN1 co-internalization with HCV particles. After interaction with the CD81-CLDN1 complex, the HCV particle also transiently activates the PI3K-AKT pathway to facilitate its entry [71]. Finally, it has also been shown that E2 binding to CD81 induces Rho GTPases signalling which in turn leads to a rearrangement of the actin cytoskeleton and could therefore also affect CD81 mobility at the plasma membrane [72]. "
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    • "E2 protein participates in the recognition of viral receptors such as CD81 and SRB1 (Pileri et al., 1998; Scarselli et al., 2002). Moreover, the E2-viral receptor interactions modulate host cell functions to facilitate virus infection (Liu et al., 2012). However, it is noteworthy that there exists a subpopulation of HCV virions that is not detected by the ELASA (fraction 1.15 g/ml inFig. "
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