Contribution of the Cellular Lipid Kinase PI4KA to HCV-induced Liver Pathogenesis

 

Phosphatidylinositol-4-phosphate (PI4P) generated by phosphatidylinositol-4-kinase IIIα (PI4KA) plays a direct role in cellular trafficking and provides substrates for the synthesis of other phosphoinositides which are largely involved in signal transduction. Hepatitis C virus (HCV) is known to activate PI4KA. Recent studies showed elevated PI4KA expression in hepatocellular carcinoma, particularly associated with poor prognosis. Therefore changes in PI4KA activity and abundance might be a critical determinant in regulating tumor progression.

In this study we found that PI4KA silencing or inhibitor treatment in hepatoma cells induced changes in cell morphology due to reorganization of cytoskeletal structures. Phosphorylation of paxillin and cofilin, two important actin cytoskeletal regulators, was reduced under these conditions, resulting in less focal adhesions and lower invasiveness. The PI4KA activation upon HCV infection or expression led to opposite phenotypes with increased p-paxillin and p-cofilin, elevated focal adhesions numbers and enhanced cell invasiveness, suggesting PI4P concentration as the driving force. Evaluation of PIP synthesis pathways revealed that silencing of PIK3C2G, a lipid kinase converting PI4P to PI(3,4)P2, led to similar phenotypes observed in PI4KA-knockdown cells. Knockdown of PI4KA or PIK3C2G reduced PI(3,4)P2-containing podosome-like structures at cell plasma membrane, dampening p-AKT2. HCV infection or expression in contrast stimulated p-AKT2. Key findings were validated using immortalized hepatocytes, PHH and mice.

In conclusion, our data suggested that elevated PI4KA expression or activity promotes cellular pathways governing cell morphology, cytoskeleton dynamics and cell invasiveness, favorable for cancer progression via PI(3,4)P2 and its downstream mediator AKT2. HCV therefore potentially contributes to liver pathogenesis via activating PI4KA.

Publication History

Article published online:
26 January 2022

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