Hepatitis B virus X protein induces IKKa nuclear translocation via Akt-Dependent phosphorylation to promote the motility of hepatocarcinoma cells

Hepatitis B virus (HBV) X protein (HBx) has been implicated in HBV-associated carcinogenesis through activation of I?B kinase (IKK)/nuclear factor kappa B (NF-?B) signaling pathway. Besides activating NF-?B in the cytoplasm, IKKa was found in the nucleus to regulate gene expression epigenetically in response to various stimuli. However, it is unknown whether nuclear IKKa plays a role in HBx-associated tumor progression. Moreover, the molecular mechanism underlying IKKa nuclear transport also remains to be elucidated. Here, we disclosed HBx as a new inducer of IKKa nuclear transport in hepatoma cells. HBx induced IKKa nuclear transport in an Akt-dependent manner. HBx-activated Akt promoted IKKa nuclear translocation via phosphorylating its threonine-23 (Thr23). In addition, IKKa ubiquitination enhanced by HBx and Akt also contributed to the IKKa accumulation in the nucleus, indicating the involvement of ubiquitination in Akt-increased IKKa nuclear transport in response to HBx. Furthermore, inhibition of IKKa nuclear translocation by mutation of its nuclear localization signal and Thr23 diminished IKKa-dependent cell migration. Taken together, our findings shed light on the molecular mechanism of IKKa nuclear translocation and provide a potential role of nuclear IKKa in HBx-mediated hepatocellular carcinoma (HCC) progression. J. Cell. Physiol. 227: 1446-1454, 2012. (C) 2011 Wiley Periodicals, Inc.