Hepatitis B virus pre-S2 mutant surface antigen induces degradation of cyclin-dependent kinase inhibitor p27Kip1 through c-Jun activation domain-binding protein 1.
The hepatitis B virus (HBV) large surface antigen (LHBS) mutant with deletion at the pre-S(2) region accumulates in endoplasmic reticulum (ER) and is associated with HBV-induced hepatocellular carcinogenesis. In this study, we found that the pre-S(2) LHBS mutant directly interacts with the Jun activation domain-binding protein 1 (JAB1). Association of pre-S(2) LHBS with JAB1 dissociated JAB1 from the JAB1/IRE1 complex in ER. The free (active) JAB1 then translocated into cell nuclei and rendered the Cdk inhibitor p27(Kip1) to cytosolic proteasome for degradation. The pre-S(2) LHBS mutant induced hyperphosphorylation of tumor suppressor retinoblastoma (RB) via cyclin-dependent kinase 2 (Cdk2), a downstream molecule regulated by p27(Kip1). This effect is independent of the ER stress signaling pathway. The transgenic mice carrying the pre-S(2) mutant LHBS gene also exhibited Cdk2 activation, p27(Kip1) degradation, as well as RB hyperphosphorylation. The mouse hepatocytes exhibited morphologic abnormalities such as chromatin condensation, multinucleation, and dysplasia of hepatocytes. In summary, the pre-S(2) LHBS mutant causes p27(Kip1) degradation through direct interaction with JAB1. The pre-S(2) mutant LHBS is suggested to be a potential oncoprotein for HBV-related hepatocellular carcinoma.
Hsieh
Yi-Hsuan
YH
Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Su
Ih-Jen
IJ
Wang
Hui-Ching
HC
Tsai
Jui-He
JH
Huang
Yu-Jun
YJ
Chang
Wen-Wei
WW
Lai
Ming-Derg
MD
Lei
Huan-Yaw
HY
Huang
Wenya
W
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000075686:COP9 Signalosome Complex; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010447:Peptide Hydrolases / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism
D006514:Hepatitis B Surface Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011498:Protein Precursors; D016160:Retinoblastoma Protein; C050807:presurface protein 2, hepatitis B surface antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex