Hepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication

被引:21
作者
Yeom, Sujeong [1 ]
Jeong, Hyerin [1 ]
Kim, Soo Shin [1 ]
Jang, Kyung Lib [1 ]
机构
[1] Pusan Natl Univ, Coll Nat Sci, Dept Microbiol, Busan 46241, South Korea
基金
新加坡国家研究基金会;
关键词
hepatitis B virus; HBx; PA28; gamma; proteasome; p53; UBIQUITIN LIGASE SIAH-1; REAL-TIME PCR; HBX PROTEIN; C VIRUS; REG-GAMMA; IN-VIVO; HEPATOCELLULAR-CARCINOMA; P53-INDUCED APOPTOSIS; CORE PROTEIN; CELLULAR P53;
D O I
10.1099/jgv.0.001054
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Proteasomal activator gamma (PA28 gamma), frequently overexpressed in hepatocellular carcinoma, is believed to play important roles in tumourigenesis. However, the underlying mechanism of PA28 gamma overexpression and its possible roles in hepatitis B virus (HBV) replication are largely unknown. In the present study, we found that hepatitis B virus X protein (HBx) activates PA28 gamma expression by upregulating p53 levels in human hepatoma cells. The elevated PA28 gamma levels in turn repressed seven in absentia homologue 1 expression via downregulation of p53 levels, thereby inhibiting ubiquitin-dependent proteasomal degradation of HBx, which ultimately led to upregulation of HBx levels. The correlation among HBx, p53 and PA28 gamma was exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, knockdown of either p53 or PA28 gamma in HepG2 cells downregulated HBx levels and thereby inhibited HBV replication, whereas overexpression of p53 or PA28 gamma in Hep3B cells upregulated HBx levels, which stimulated HBV replication, indicating that p53 and PA28 gamma act as activators of HBV replication. In conclusion, HBx levels are upregulated via a positive feedback loop involving p53 and PA28 gamma to stimulate HBV propagation.
引用
收藏
页码:655 / 666
页数:12
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[31]   DISRUPTION OF THE FUNCTION OF TUMOR-SUPPRESSOR GENE P53 BY THE HEPATITIS-B VIRUS X-PROTEIN AND HEPATOCARCINOGENESIS [J].
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TSUCHIDA, N ;
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KOIKE, K .
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[32]   P53 EXPRESSION IN HEPATOCELLULAR-CARCINOMA IN A POPULATION IN SINGAPORE WITH ENDEMIC HEPATITIS-B VIRUS-INFECTION [J].
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[40]   Hepatitis B virus X protein suppresses all-trans retinoic acid-induced apoptosis in human hepatocytes by repressing p14 expression via DNA methylation [J].
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