| RRC ID |
46485
|
| 著者 |
Geng X, Harry BL, Zhou Q, Skeen-Gaar RR, Ge X, Lee ES, Mitani S, Xue D.
|
| タイトル |
Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca2+ increase and cell death in Caenorhabditis elegans.
|
| ジャーナル |
Proc Natl Acad Sci U S A
|
| Abstract |
HBx is a multifunctional hepatitis B virus (HBV) protein that is crucial for HBV infection and pathogenesis and a contributing cause of hepatocyte carcinogenesis. However, the host targets and mechanisms of action of HBx are poorly characterized. We show here that expression of HBx in Caenorhabditis elegans induces both necrotic and apoptotic cell death, mimicking an early event of liver infection by HBV. Genetic and biochemical analyses indicate that HBx interacts directly with the B-cell lymphoma 2 (Bcl-2) homolog CED-9 (cell death abnormal) through a Bcl-2 homology 3 (BH3)-like motif to trigger both cytosolic Ca(2+) increase and cell death. Importantly, Bcl-2 can substitute for CED-9 in mediating HBx-induced cell killing in C. elegans, suggesting that CED-9 and Bcl-2 are conserved cellular targets of HBx. A genetic suppressor screen of HBx-induced cell death has produced many mutations, including mutations in key regulators from both apoptosis and necrosis pathways, indicating that this screen can identify new apoptosis and necrosis genes. Our results suggest that C. elegans could serve as an animal model for identifying crucial host factors and signaling pathways of HBx and aid in development of strategies to treat HBV-induced liver disorders.
|
| 巻・号 |
109(45)
|
| ページ |
18465-70
|
| 公開日 |
2012-11-6
|
| DOI |
10.1073/pnas.1204652109
|
| PII |
1204652109
|
| PMID |
23091037
|
| PMC |
PMC3494929
|
| MeSH |
Amino Acid Motifs
Amino Acid Sequence
Animals
Caenorhabditis elegans / cytology*
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / chemistry
Caenorhabditis elegans Proteins / metabolism*
Calcium / metabolism*
Cytosol / metabolism
Genes, Suppressor
Intracellular Space / metabolism*
Mitochondria / metabolism
Molecular Sequence Data
Mutation / genetics
Necrosis
Permeability
Protein Binding
Proto-Oncogene Proteins c-bcl-2 / chemistry
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Signal Transduction
Trans-Activators / chemistry
Trans-Activators / genetics
Trans-Activators / metabolism*
Viral Regulatory and Accessory Proteins
|
| IF |
9.412
|
| 引用数 |
27
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 線虫 |
tm4559
tm690
tm4171 |
