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 cellular proteins from the nucleus to the cytoplasm. The nuclear export receptor Crm1 is essential in this process by recognizing the NES motif. Here, we show that the oncogenic hepatitis B virus (HBV) X protein (HBx) contains a functional NES motif. We found that the predominant cytoplasmic localization of HBx is sensitive to the drug leptomycin B (LMB), which specifically inactivates Crm1. Mutations at the two conserved leucine residues to alanine at the NES motif (L98A,L100A) resulted in a nuclear redistribution of HBx. A recombinant HBx protein binds to Crm1 in vitro. In addition, ectopic expression of HBx sequesters Crm1 in the cytoplasm. Furthermore, HBx activates NFkappaB by inducing its nuclear translocation in a NES-dependent manner. Abnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localization of NFkappaB, was also observed in hepatocytes from HBV-positive liver samples with chronic active hepatitis. We suggest that Crm1 may play a role in HBx-mediated liver carcinogenesis.
Forgues
M
M
Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Marrogi
A J
AJ
Spillare
E A
EA
Wu
C G
CG
Yang
Q
Q
Yoshida
M
M
Wang
X W
XW
D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D006515:Hepatitis B virus / Q000302:isolation & purification; D006801:Humans; D028884:Karyopherins; D008099:Liver / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D000097606:Exportin 1 Protein
D002352:Carrier Proteins; D017931:DNA Primers; D028884:Karyopherins; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D000097606:Exportin 1 Protein; C057628:hepatitis B virus X protein