PI3K-Akt signaling pathway upregulates hepatitis C virus RNA translation through the activation of SREBPs

- Akt three isoforms upregulate HCV RNA translation dependent upon PI3K.
- Upregulation of HCV translation by Akts requires their kinase activity.
- HCV 3′UTR is not involved in translation modulation by Akt.
- HCV NS5A enhances viral translation in the absence of 3′UTR via PI3K-Akt activation.
- SREBPs are downstream effectors for HCV translation modulation by Akt.

Hepatitis C virus (HCV) activates PI3K-Akt signaling to enhance entry and replication. Here, we found that this pathway also increased HCV translation. Knocking down the three Akt isoforms significantly decreased, whereas ectopic expression increased HCV translation. HCV translation upregulation by Akt required their kinase activities because Akt kinase-dead mutants downregulated HCV translation; and was dependent on PI3K activity since it was sensitive to PI3K inhibitor wortmannin. The viral 3′UTR was not involved in translation upregulation by Akt. HCV NS5A increased Akt phosphorylation/activity and HCV translation in the absence of the viral 3′UTR. Sterol regulatory element-binding proteins (SREBPs) were the downstream effectors of the PI3K-Akt pathway in regulating HCV translation because Akt1 and Akt2 activated both SREBP-1 and SREBP-2, whereas Akt3 upregulated SREBP-1. Knocking down SREBPs significantly decreased, while ectopic expression of SREBPs increased HCV translation. Taken together, we showed that the PI3K-Akt signaling pathway positively regulates HCV translation through SREBPs.