Hepatitis B virus replication and sex-determining region Y box 4 production are tightly controlled by a novel positive feedback mechanism

Abstract

Hepatitis B virus (HBV) infection is a major cause of liver diseases. However, the mechanisms underlying HBV infection and pathogenesis remain largely unknown. The sex-determining region Y box 4 (Sox4) is a transcriptional factor, which preferentially regulates the development of various organs, tissues, and cancers. But, the role of Sox4 in viral infection and pathogenesis has not been elucidated. Here, we demonstrated that Sox4 is up-regulated by HBV, and revealed the mechanism by which HBV regulates Sox4 expression. First, HBV stimulates Sox4 expression through transcriptional factor Yin Yang 1 (YY1), which binds to Sox4 promoter to activate Sox4 transcriptional activity. Second, miR-335, miR-129-2 and miR-203 inhibit Sox4 expression by targeting its mRNA 3’UTR, while HBV suppresses the microRNAs expression, resulting in up-regulating Sox4 post-transcriptionally. Third, Sox4 protein is degraded by proteasome, while HBV surface protein (HBsAg) prevents Sox4 from degradation by directly interacting with the protein, thereby enhancing Sox4 production post-translationlly. More interestingly, HBV-activated Sox4 in turn facilitates HBV replication by direct binding to the viral genome via its HMG box. Thus, this study revealed a novel positive feedback mechanism by which Sox4 production and HBV replication are tightly correlated.

The lncRNA CASC15 regulates SOX4 expression in RUNX1-rearranged acute leukemia

“…This region contains three putative binding sites for the transcription factor YY1 [36]. Dual luciferase reporter assays in HEK 293 T cells, with constitutive expression of CASC15 , caused increased SOX4 promoter activity (Additional file 7: Figure S5d).…”

Multifunctional YY1 in Liver Diseases

“…The sex-determining region Y box 4 (Sox4) is a TF that preferentially regulates the development of various organs, tissues, and cancers. In a cDNA microarray study by Shang et al, 8 Sox4 expression was found to be closely related to HBV replication network. The investigators further showed that HBV stimulates upregulated expression of Sox4 through the indispensable YY1 protein, which is itself upregulated by HBV through MAPK signaling and binds to the Sox4 promoter to activate Sox4 transcriptional activity.…”

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

“…Studies have indicated that YY1 regulates other signaling pathways that facilitate HBV replication. Shang et al discovered that YY1 activates the sex-determining region Y box 4 protein in HepG2 cells with opposing results in control cells, suggesting a role in HBV replication [185].…”