title: The HBx oncoprotein of hepatitis B virus deregulates the cell cycle by promoting the intracellular accumulation and re-compartmentalization of the cellular deubiquitinase USP37.
abstract: The HBx oncoprotein of hepatitis B Virus has been accredited as one of the protagonists in driving hepatocarcinogenesis. HBx exerts its influence over the cell cycle progression by potentiating the activity of cyclin A/E-CDK2 complex, the Cyclin A partner of which is a well-known target of cellular deubiquitinase USP37. In the present study, we observed the intracellular accumulation of cyclin A and USP37 proteins under the HBx microenvironment. Flow cytometry analysis of the HBx-expressing cells showed deregulation of cell cycle apparently due to the enhanced gene expression and stabilization of USP37 protein and deubiquitination of Cyclin A by USP37. Our co-immunoprecipitation and confocal microscopic studies suggested a direct interaction between USP37 and HBx. This interaction promoted the translocation of USP37 outside the nucleus and prevented its association and ubiquitination by E3 ubiquitin ligases - APC/CDH1 and SCF/β-TrCP. Thus, HBx seems to control the cell cycle progression via the cyclin A-CDK2 complex by regulating the intracellular distribution and stability of deubiquitinase USP37.
authors.affiliation: Virology Group, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: Nehul
authors.initials: N
authors.lastname: Saxena
authors.affiliation: Virology Group, International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
mesh_terms: D021581:Active Transport, Cell Nucleus; D064200:Cdh1 Proteins / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D064200:Cdh1 Proteins; D019925:Cyclin A; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D010450:Endopeptidases; C559980:USP37 protein, human