Hepatitis B virus X protein enhances liver cancer cell migration by regulating calmodulin-associated actin polymerization
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초록
Hepatitis B virus (HBV) infection is a major cause of hepatocellularcarcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, playspivotal roles in the development and metastasis of HCC. It hasbeen reported that HBx induces liver cancer cell migration andreorganizes actin cytoskeleton, however the molecular basisfor actin cytoskeleton reorganization remains obscure. In thisstudy, we for the first time report that HBx promotes actinpolymerization and liver cancer cell migration by regulatingcalcium modulated protein, calmodulin (CaM). HBx physicallyinteracts with CaM to control the level of phosphorylated cofilin,an actin depolymerizing factor. Mechanistically, HBx interactswith CaM, liberates Hsp90 from its inhibitory partner CaM,and increases the activity of Hsp90, thus activating LIMK1/cofilinpathway. Interestingly, the interaction between HBx and CaMis calcium-dependent and requires the CaM binding motif onHBx. These results indicate that HBx modulates CaM whichplays a regulatory role in Hsp90/LIMK1/cofilin pathway of actinreorganization, suggesting a new mechanism of HBV-inducedHCC metastasis specifically derived by HBx.
Abstract
Hepatitis B virus (HBV) infection is a major cause of hepatocellularcarcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, playspivotal roles in the development and metastasis of HCC. It hasbeen reported that HBx induces liver cancer cell migration andreorganizes actin cytoskeleton, however the molecular basisfor actin cytoskeleton reorganization remains obscure. In thisstudy, we for the first time report that HBx promotes actinpolymerization and liver cancer cell migration by regulatingcalcium modulated protein, calmodulin (CaM). HBx physicallyinteracts with CaM to control the level of phosphorylated cofilin,an actin depolymerizing factor. Mechanistically, HBx interactswith CaM, liberates Hsp90 from its inhibitory partner CaM,and increases the activity of Hsp90, thus activating LIMK1/cofilinpathway. Interestingly, the interaction between HBx and CaMis calcium-dependent and requires the CaM binding motif onHBx. These results indicate that HBx modulates CaM whichplays a regulatory role in Hsp90/LIMK1/cofilin pathway of actinreorganization, suggesting a new mechanism of HBV-inducedHCC metastasis specifically derived by HBx.
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