Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signalling by ginsenoside Rg3 attenuates hepatitis B virus replication

Abstract

In present study, we investigated the effect of ginsenoside Rg3 on hepatitis B virus DNA replication and secretion of hepatitis B surface antigen and e antigen in HepG2.2.15 cells. Rg3 dose- and time-dependently inhibited hepatitis B surface antigen, e antigen, and hepatitis B viral particle secretion. To explore the effect of Rg3 on anti-hepatitis B activity, we analysed toll-like receptor-myeloid differentiation primary response gene 88 signalling. Rg3 did not affect the expression of toll-like receptors or myeloid differentiation primary response gene 88. However, it significantly inhibited the expression of TNF receptor-associated factor 6 and transforming growth factor β activated kinase-1, which are adaptor molecules that signal through a toll-like receptor-myeloid differentiation primary response gene 88-dependent pathway. The inhibitory effect of Rg3 on TNF receptor-associated factor 6/transforming growth factor β activated kinase-1 expression was caused by the downregulation of TNF receptor-associated factor 6 expression as well as the stimulation of ubiquitination and proteasomal degradation of TNF receptor-associated factor 6, followed by downregulation of transforming growth factor β activated kinase-1. Furthermore, Rg3 inhibited mitogen-activated protein kinase signalling by inhibiting c-Jun N-terminal kinase phosphorylation, reduced the expression of AP-1 transcription factors (especially c-Jun and JunB), and inhibited AP-1 promoter activity. The inhibitory effect of Rg3 on c-Jun N-terminal kinase/AP-1 signalling showed anti-inflammatory activity based on the reduction in the expression of pro-inflammatory cytokines, IL-8 and TNF-α, at both the transcriptional and translational levels. Therefore, Rg3 showed anti-hepatitis B activity via the degradation of TNF receptor-associated factor 6/transforming growth factor β activated kinase-1 and the inhibition of c-Jun N-terminal kinase/AP-1 signalling.

Keywords: Ginsenoside Rg3; Hepatitis B virus; TAK1; TRAK6; Ubiquitination.