Interaction of the hepatitis B virus X protein with the Crm1-dependent nuclear export pathway

The leucine-rich nuclear export signal (NES) is used to shuttle large cellu lar proteins from the nucleus to the cytoplasm. The nuclear export receptor Crm1 is essential in this process by recognizing the NES motif. Here, we s how that the oncogenic hepatitis B virus (HBV)X protein (HBx) contains a fu nctional NES motif. We found that the predominant cytoplasmic localization of HBx is sensitive to the drug leptomycin B (LMB), which specifically inac tivates Crm1. Mutations at the two con served leucine residues to alanine a t the NES motif (L98A,L100A) resulted in a nuclear redistribution of HBx. A recombinant HBx protein binds to Crm1 in vitro. In addition, ectopic expre ssion of HBx sequesters Crm1 in the cytoplasm. Furthermore, HBx activates N F kappaB by inducing its nuclear translocation in a NES-dependent manner. A bnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localiz ation of NF kappaB, was also observed in hepatocytes from HBV-positive live r samples with chronic active hepatitis. We suggest that Crm1 may play a ro le in HBx-mediated liver carcinogenesis.