Zinc-dependent interaction between JAB1 and pre-S2 mutant large surface antigen of hepatitis B virus and its implications for viral hepatocarcinogenesis.
Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The pre-S2 mutant large HBV surface protein (Δ2 LHBS), which contains an in-frame deletion of approximately 17 amino acids in LHBS, is highly associated with risks and prognoses of HBV-induced HCC. It was previously reported that Δ2 LHBS interacts with the Jun activation domain-binding protein 1 (JAB1), a zinc metalloprotease. This promotes the degradation of the cell cycle regulator p27(Kip1) and is believed to be the major mechanism for Δ2 LHBS-induced HCC. In this study, it was found that the interaction between JAB1 and Δ2 LHBS is facilitated by divalent metal Zn(2+) ions. The binding of JAB1 to Δ2 LHBS requires the JAB1/CSN5 MPN metalloenzyme (JAMM) motif and residue H138 that binds to Zn(2+) ions in JAB1. Isothermal titration calorimetry showed that Δ2 LHBS binds directly to Zn(2+) ions in a two-site binding mode. Residues H71 and H116 in Δ2 LHBS, which also contact Zn(2+) ions, are also indispensable for Δ2 LHBS-mediated p27(Kip1) degradation in human HuH7 cells. These results suggest that developing drugs that interrupt interactions between Δ2 LHBS and JAB1 can be used to mitigate Δ2 LHBS-associated risks for HCC.
Department of Medical Laboratory Science and Biotechnology.
Jye-Lin
JL
Hsu
Woei-Jer
WJ
Chuang
Ih-Jen
IJ
Su
Wen-Jun
WJ
Gui
Yu-Ying
YY
Chang
Yun-Ping
YP
Lee
Yu-Lin
YL
Ai
David T
DT
Chuang
Wenya
W
Huang
D020816:Amino Acid Motifs; D000075686:COP9 Signalosome Complex; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000821:virology; D045744:Cell Line, Tumor; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D019694:Hepatitis B, Chronic / Q000201:enzymology* / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000821:virology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D006514:Hepatitis B Surface Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011498:Protein Precursors; C050807:presurface protein 2, hepatitis B surface antigen; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D015032:Zinc