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.
Highlights
Introduction HepatitisB virus (HBV), chronically infecting estimated257 million people worldwide, is one of the most important etiological factors causing hepatitis and hepatic injury[1]
We have demonstrated that B56γ was upregulated and positively correlated with Hepatitis B virus X (HBx) expression in the specimens of liver diseases’ patients, hepatitis B virus (HBV)-infected primary human hepatocytes (PHHs) in human-liver-chimeric (HLC) mice, HBx-transgenic (Tg) mice, HBV-infected HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP), and several HBx-expressing hepatic cells
In order to explore the relationship between PPP2R5C expression and HBV infection, a genomic expression data set of chronic hepatitis B (CHB) patients was employed
Summary
Introduction HepatitisB virus (HBV), chronically infecting estimated257 million people worldwide, is one of the most important etiological factors causing hepatitis and hepatic injury[1]. Chronic HBV infection leads to progressive complications via several molecular mechanisms and (HBx), which is a multifunctional regulator of transcriptional regulation, apoptosis, and cell cycle[5]. Among these functions, the transcriptional regulation may play an important role in HBV infection-induced hepatic injury, because HBx activates numerous signaling pathways linked to inflammation, immune response, and cell deaths[6,7]. Official journal of the Cell Death Differentiation Association. 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, apoptosis, response to stress, and tumor suppression[8]. Chen et al.[14] demonstrated that B56γ of the PP2A holoenzyme was replaced by Simian virus 40 (SV40) small T antigen to facilitate cellular transformation
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