Stimulating DDX3 expression by serotonin 5-HT receptor 7 through phosphorylation of p53 via the AC-PKA-ERK signaling pathway.

DDX3 is a host viral factor that can inhibit the hepatitis B virus-induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5-HT upregulated DDX3 promoter activity via the 5-HT₇ receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription-polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5-HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5-HT₇ receptor by transfection si-5-HT₇ receptors or si-control into HepG2 cells treated by 5-HT (or 5-HT plus agonist) confirmed the role of the 5-HT₇ receptor in DDX3 expression. The IFN-β-Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5-HT₇ agonist (AS-19) increased IFN-β expression and inhibited HBV replication. Luciferase assays showed the involvement of 5-HT₇ receptors in DDX3 expression via pathways by using protein kinase A and adenylyl cyclase inhibitor (MDL 12330A). AS-19 mediated DDX3 promoter activated extracellular signal-regulated kinase ERK signaling the p53 phosphorylation (-1080/-1070) resulted in upregulation of DDX3 promoter transactivation via the 5-HT₇ receptors agonist. Overall, 5-HT₇ was found to be a new potential target to inhibit hepatitis B infection by activating pathways by phosphorylating p53 via the 5-HT₇ agonist response by mediating DDX3 expression.

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