Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal

Kyun Hwan Kim, Baik L. Seong

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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 I (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.

Original languageEnglish
Pages (from-to)2104-2116
Number of pages13
JournalEMBO Journal
Volume22
Issue number9
DOIs
Publication statusPublished - 2003 May 1

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Viruses
Hepatitis B virus
Apoptosis
Caspase 8
Liver
Liver Diseases
Death Domain Receptor Signaling Adaptor Proteins
Tumor Necrosis Factor-alpha
Caspase Inhibitors
Deregulation
Cell growth
Liver Neoplasms
Caspase 3
Anti-Idiotypic Antibodies
Hepatocytes
Genes
Chemical activation
hepatitis B virus X protein
Genome

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

@article{80be432673c74193bd253aec71d0af18,
title = "Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal",
abstract = "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 I (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.",
author = "Kim, {Kyun Hwan} and Seong, {Baik L.}",
year = "2003",
month = "5",
day = "1",
doi = "10.1093/emboj/cdg210",
language = "English",
volume = "22",
pages = "2104--2116",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "9",

}

Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal. / Kim, Kyun Hwan; Seong, Baik L.

In: EMBO Journal, Vol. 22, No. 9, 01.05.2003, p. 2104-2116.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal

AU - Kim, Kyun Hwan

AU - Seong, Baik L.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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 I (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.

AB - 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 I (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.

UR - http://www.scopus.com/inward/record.url?scp=0038558163&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038558163&partnerID=8YFLogxK

U2 - 10.1093/emboj/cdg210

DO - 10.1093/emboj/cdg210

M3 - Article

C2 - 12727877

AN - SCOPUS:0038558163

VL - 22

SP - 2104

EP - 2116

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 9

ER -