ER应激调节蛋白磷酸酶2A-B56γ，乙型肝炎病毒X蛋白靶向，诱

StephenW

Cell Death Dis. 2018 Jul 9;9(7):762. doi: 10.1038/s41419-018-0787-3.
ER stress regulating protein phosphatase 2A-B56γ, targeted by hepatitis B virus X protein, induces cell cycle arrest and apoptosis of hepatocytes.
He C1, Qiu Y1, Han P1, Chen Y1, Zhang L1, Yuan Q1, Zhang T1, Cheng T1, Yuan L1, Huang C1, Zhang S2, Yin Z2, Peng XE3, Liang D4, Lin X3, Lin Y5, Lin Z6, Xia N1.
Author information

1
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
2
    Department of Hepatobiliary Surgery, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University Affiliated Zhongshan Hospital, Xiamen, China.
3
    Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
4
    Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
5
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China. [email protected].
6
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China. [email protected].

Abstract

Hepatitis B virus X (HBx) protein contributes to the progression of hepatitis B virus (HBV)-related hepatic injury and diseases, but the exact mechanism remains unclear. Protein phosphatase 2 A (PP2A) is a major serine/threonine phosphatase involved in regulating many cellular phosphorylation signals that are important for regulation of cell cycle and apoptosis. Does HBx target to PP2A-B56γ and therefore affect HBx-induced hepatotoxicity? In the present study, the expression of B56γ positively correlated with the level of HBx in HBV-infected primary human hepatocytes in human-liver-chimeric mice, HBx-transgenic mice, HBV-infected cells, and HBx-expressing hepatic cells. B56γ promoted p53/p21-dependent cell cycle arrest and apoptosis. Mechanistically, B56γ was transactivated by AP-1, which was under the regulation of endoplasmic reticulum (ER) stress induced CREBH signaling in HBx-expressing hepatic cells. B56γ dephosphorylated p-Thr55-p53 to trigger p53/p21 pathway-dependent cell cycle G1 phase arrest, resulting in apoptosis of hepatic cells. In conclusion, this study provides a novel insight into a mechanism of B56γ mediating cell cycle arrest and apoptosis of HBx-expressing hepatic cells and a basis for B56γ being a potential therapeutic target for HBV-infected hepatic cells.

PMID:
    29988038
DOI:
    10.1038/s41419-018-0787-3

StephenW

细胞死亡病2018年7月9日; 9（7）：762。 doi：10.1038 / s41419-018-0787-3。
ER应激调节蛋白磷酸酶2A-B56γ，乙型肝炎病毒X蛋白靶向，诱导细胞周期停滞和肝细胞凋亡。
他C1，邱Y1，韩P1，陈Y1，张L1，袁Q1，张T1，程T1，袁L1，黄C1，张S2，尹Z2，彭X3，梁D4，林X3，林Y5，林Z6 ，夏娜。
作者信息

1
    厦门大学公共卫生学院分子疫苗学与分子诊断国家重点实验室，厦门
2
    厦门大学附属中山医院福建省慢性肝病和肝细胞癌重点实验室，肝胆外科，厦门
3
    福建医科大学基础医学院胃肠癌教育部重点实验室，福州
4
    福建医科大学孟超肝胆外科医院，福州
五
    厦门大学公共卫生学院分子疫苗学与分子诊断国家重点实验室，厦门[email protected]。
6
    厦门大学公共卫生学院分子疫苗学与分子诊断国家重点实验室，厦门[email protected]。

抽象

乙型肝炎病毒X（HBx）蛋白有助于乙型肝炎病毒（HBV）相关的肝损伤和疾病的进展，但确切的机制仍不清楚。蛋白磷酸酶2A（PP2A）是一种主要的丝氨酸/苏氨酸磷酸酶，参与调节许多细胞磷酸化信号，这些信号对细胞周期和细胞凋亡的调节很重要。 HBx是否针对PP2A-B56γ并因此影响HBx诱导的肝毒性？在本研究中，B56γ的表达与人肝嵌合小鼠，HBx转基因小鼠，HBV感染细胞和HBx表达肝细胞中HBV感染的原代人肝细胞中的HBx水平正相关。 B56γ促进p53 / p21依赖性细胞周期阻滞和凋亡。在机制上，B56γ被AP-1反式激活，其在表达HBx的肝细胞中受内质网（ER）应激诱导的CREBH信号传导的调节。 B56γ去磷酸化p-Thr55-p53触发p53 / p21通路依赖性细胞周期G1期阻滞，导致肝细胞凋亡。总之，本研究为B56γ介导HBx表达肝细胞的细胞周期停滞和凋亡的机制提供了新的见解，并为B56γ作为HBV感染的肝细胞的潜在治疗靶点奠定了基础。

结论：
    29988038
DOI：
    10.1038 / s41419-018-0787-3