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Pro‐apoptotic function of HBV X protein is mediated by interaction with c‐FLIP and enhancement of death‐inducing signal
Author(s) -
Kim KyunHwan,
Seong Baik L.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg210
Subject(s) - biology , flip , apoptosis , microbiology and biotechnology , function (biology) , signal (programming language) , virology , cancer research , genetics , computer science , programming language
Despite its implication in the progression of hepatitis B virus (HBV)‐associated liver disease, the pro‐apoptotic function of HBx protein remains poorly understood. We show that the expression of HBx leads to hyperactivation of caspase‐8 and caspase‐3 upon treatment with tumor necrosis factor‐α (TNF‐α) or anti‐Fas antibody, and this activation is correlated with the sensitivity to apoptosis. We demonstrate cytoplasmic co‐localization and direct interaction between HBx and the cellular FLICE inhibitory protein (c‐FLIP), a key regulator of the death‐inducing signaling complex (DISC). Deletion analysis shows that the death effector domain 1 (DED1) of c‐FLIP is important for the observed interaction. Overexpression of c‐FLIP rescued the cells from HBx‐mediated apoptosis, with both the full‐length HBV genome and HBx expression vectors. Moreover, c‐FLIP and caspase‐8 inhibitor considerably protected cells from HBx‐mediated apoptosis. These data suggest that HBx abrogates the apoptosis‐inhibitory function of c‐FLIP and renders the cell hypersensitive towards the TNF‐α apoptotic signal even below threshold concentration. This provides a novel mechanism for deregulation of hepatic cell growth in HBV patients and a new target for intervention in HBV‐associated liver cancer and disease.