TY - JOUR
T1 - Interaction of the Hepatitis B Virus X Protein with the Crm1-dependent Nuclear Export Pathway
AU - Forgues, Marshonna
AU - Marrogi, Aizen J.
AU - Spillare, Elisa A.
AU - Wu, Chuan Ging
AU - Yang, Qin
AU - Yoshida, Minoru
AU - Wang, Xin Wei
PY - 2001/6/22
Y1 - 2001/6/22
N2 - 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 NFκB by inducing its nuclear translocation in a NES-dependent manner. Abnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localization of NFκB, 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.
AB - 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 NFκB by inducing its nuclear translocation in a NES-dependent manner. Abnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localization of NFκB, 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.
UR - http://www.scopus.com/inward/record.url?scp=0035933725&partnerID=8YFLogxK
U2 - 10.1074/jbc.M101259200
DO - 10.1074/jbc.M101259200
M3 - Article
C2 - 11287420
AN - SCOPUS:0035933725
SN - 0021-9258
VL - 276
SP - 22797
EP - 22803
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -