Hepatitis B Virus X Protein Regulates Orphan Nuclear Receptor Nur77 Protein Stability

Primary liver cancer is one of the top three malignant tumors in the global cancer mortality rate.Chronic hepatitis B virus(HBV)infection and chronic liver disease have become a major cause of primary liver cancer.HBx is an X protein encoded by the HBV genome.It has the dual effects of promoting proliferation and inhibiting apoptosis.It is closely related to the malignant progression of liver cancer and is also a factor for drug resistance of liver cancer.Nur77 is an important drug target in many tumors.A large number of compounds can induce Nur77 expression and mediate its anti-cancer effect through Nur77.It has been reported that Nur77 expression is lower in liver cancer,one of the reasons is caused by Snail-mediated methylation.Because liver cancer is mainly related to hepatitis B,this topic focuses on whether HBx affects the expression of Nur77.First of all,testing clinical specimens of liver cancer,we found that HBx expression was negatively correlated with Nur77 expression.At the cellular level,transfection of HBx induces ubiquitination and degradation of Nur77.This effect can be reversed by the proteasome inhibitor MG132,indicating that HBx induces Nur77 degradation via the UPS pathway.Through immunoprecipitation experiments,we identified the existence of interaction between Nur77 and HBx,and through mutant analysis,identified the interaction domain of the two,the interaction region is located in the ligand binding domain of Nur77 and the carbon-terminal structure of HBx area.Finally,we identified the E3 ligase of HBx-induced Nur77 ubiquitination,and the results suggest that HBx-induced degradation of Nur77 is related to CUL4A/B.The subject revealed for the first time that HBx regulates the expression of Nur77.The research findings of this topic will help to reveal the mechanism of HBx in promoting liver cancer and provide a theoretical basis for the development of new anti-liver cancer treatment.