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

Abstract

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 cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS‐19 mediated DDX3 promoter activated PKA 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 AC/PKA/ERK pathways by phosphorylating p53 via the 5‐HT7 agonist response by mediating DDX3 expression.

Perturbation Analysis of a Prognostic DDX3X-Mediated Gene Expression Signature Identifies the Antimetastatic Potential of Chaetocin in Hepatocellular Carcinoma

“…Actually, ATP-dependent RNA helicase DDX3X appeared to be modulated by several compounds and cytokines via direct and/or indirect interactions. In liver hepatocellular cells, previous findings indicated that 5-HT treatment could augment 5-HT receptor 7-mediated DDX3X promoter activity as well as the induction of an innate immunity to abolish hepatitis B virus (HBV) infection [ 27 ]. Another research finding in hepatocellular HepG2 cells demonstrated that the addition of tazemetostat, SP2509, decitabine and trichostatin A led to the downregulation of DDX3X RNA [ 28 ].…”

The janus face of serotonin: Regenerative promoter and chronic liver disease aggravator

“…Kang et al confirmed that the activation of 5-HTR 7 by 5-HT stimulated the expression of DDX3 through adenylate cyclase (AC)/protein kinase A (PKA)/extracellular regulated protein kinases (ERK)-mediated phosphorylation of p53, thereby inhibiting HBV replication. These findings highlight the potential of targeting 5-HTR 7 as a strategy to suppress HBV infection [ 9 ].…”

“…However, since the 21st century, there has been an increasing exploration of the role of 5-HT in liver diseases. From hepatitis [ 9 ], fatty liver [ 10 ] and acute liver injury [ 11 ] to cirrhosis [ 12 ] and liver cancer [ 13 ], the involvement of 5-HT has been identified as a significant and noteworthy contribution. However, the role of 5-HT in the liver is complex and seems contradictory, as it has the potential to both promote hepatic regeneration and accelerate tumor growth [ 14 ].…”

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

“…In human monocyte-derived macrophages, the IL-1β, LPS-and TNF-α-dependent NF-κB, and JNK signaling pathways were blocked by Zc3h12a [67]. In liver hepatocellular cells, 5-HT treatment increased 5-HT receptor 7-dependent DDX3X promoter activity, along with downstream expression, to induce innate immunity against hepatitis B virus (HBV) infection [68]. Activation of innate immune response through the TBK1/IKKε/IRF3 signaling axis was also observed by the ginsenoside Rg3 stimulus, which increased Akt-p53-dependent DD3X promoter transactivation and its expression level [69].…”