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.