| Hepatocellular carcinoma (HCC) is one of the major malignant diseases in many healthcare systems, and it is the fifth most common cancer and the third most important cause of cancer related death in men. HCC can be induced by various factors. Infection of hepatitis B virus (HBV) or heptatitis C virus (HCV) is a major factor leading to HCC. More than 2 billion people were infected by HBV till now. Among them,24 million are chronic HBV infection patients.750 thousand people die from HBV infection each year. 650 thousands die from HCC caused by Chronic HBV infection and 100 thousands die from acute infection. There have been a lot of researches on HBV, but the exact mechanism of the pathogenesis is still not well konw.In the process of viral infection, viral proteins and host proteins induced by virus are used for virus replication and immunal escape. But, the hosts also defense the infection of virus through their immune system. Innate immune system is a non-specific immunal process and can defense various pathogens’infection. Pattern recognition receptors (PRRs) are the key components in innate immune system by recognizing pathogens and starting transduction of immunal signals. TLR family contains the most PRRs and was found earliest. When interacting with their ligands, TLRs recruit the adaptors for transduction of signals and finally activate NF-κB and IRF3/7 for regulating interferon (IFN) expression. Expression of interferon will lead to production of hundreds of interferon stimulated genes (ISGs), which will defense the infection of pathogens.Sox4 is a transcription factor that contains a conserved high-mobility group (HMG) that binds preferentially to targeted genes, and a transactivation domain (TAD) that activates gene transcription. It is related to tissue development, organofaction, cell proliferation and tumor formation. There have been a lot of researches focusing on the function of Sox4 in tumor formation, such as gastric carcinoma, prostatic carcinoma, leukemia, melanoma, hepatic carcinoma, colorectal carcinoma, breast carcinoma, and so on. Rencetly, Sox4 was reported to inhibit expression of IL-17 and IL-5. But there are no any reports on Sox4 in viral replication and innate immune response.Here, we revealed that Hepatitis B virus (HBV) infection induces Sox4 expression in three ways:At transcriptional level, HBV infection activates YY1 through MAPK signaling, which then binds to Sox4 promoter to activate Sox4 expression. At post-transcriptional level, HBV promotes Sox4 expression by suppressing expressions of miR-335, miR-129-2 and miR-203. At protein level, HBV surface protein (HBs) prevents SOX4 from Ubiquitin related degradation by directly interacting with it.In turn, we also demonstrated Sox4 can promote HBV replication in cultured cell lines. We found a Sox4 binding site in HBV genomic DNA through software analysis and the binding of Sox4 to HBV genomic DNA was confirmed by ChIP and EMSA assay. Then, it was found that the binding of Sox4 to HBV genomic DNA was necessary for Sox4 promoting HBV replication.Next, it was confirmed that Sox4 can be induced not only by HBV, but also HCV, IAV, VSV and EV71. Also, we revealed that Sox4 can promote those viruses’ replication in cultured cells, and the mechanism was due to Sox4’s global inhibition function in host innate immune response. We decide Sox4 as a key regulator in Toll like receptor (TLR) signaling pathway by suppressing expressions of TLRs, inhibiting phosphorylation of IKK complex though interacting with IKK complex, and promoting ubiqutin-related degradation of NF-κB, IRF3 and IRF7. All this finally lead to inhibition on IFN and ISGs expression and facilitation on viral replication.In this article, we firstly revealed the mechanism of virus infection and Sox4 expression. Also, we confirmed the key role of Sox4 in HBV replication. The most important things we found are the new functions of Sox4 in inhibiting interferon expression and TLR signaling transduction, which will lead to a new research fields on Sox4. |
