Zinc-dependent interaction between JAB1 and Pre-S2 mutant large surface antigen of hepatitis B virus and its implications for viral hepatocarcinogenesis

Jye Lin Hsu, Woei Jer Chuang, Ih Jen Su, Wen Jun Gui, Yu Ying Chang, Yun Ping Lee, Yu Lin Ai, David T. Chuang, Wenya Huang

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 p27Kip1 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 Zn2+ ions. The binding of JAB1 to Δ2 LHBS requires the JAB1/CSN5 MPN metalloenzyme (JAMM) motif and residue H138 that binds to Zn2+ ions in JAB1. Isothermal titration calorimetry showed that Δ2 LHBS binds directly to Zn2+ ions in a two-site binding mode. Residues H71 and H116 in Δ2 LHBS, which also contact Zn2+ ions, are also indispensable for Δ2 LHBS-mediated p27Kip1 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.

Original languageEnglish (US)
Pages (from-to)12675-12684
Number of pages10
JournalJournal of virology
Volume87
Issue number23
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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