Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2.
The hepatitis B virus X protein (HBx) is essential for viral infection and strongly interferes with cell growth and viability in culture. These activities involve interaction of HBx with the DDB1 subunit of UV-damaged DNA-binding factor UV-DDB. UV-DDB consists of DDB1 and a DDB2 subunit that mediates nuclear import and has recognized functions in DNA repair and E2F1-mediated transcription. Here we show that HBx retains DDB1-binding-dependent cytotoxic activities when engineered to accumulate in the nucleus but not when excluded from the nucleus. Nuclear localization of HBx does not require binding to DDB1 and remains unaffected by ectopically expressed UV-DDB subunits, indicating that HBx reaches the nuclear compartment independently of UV-DDB. Unexpectedly, HBx appears to largely exist in association with DDB1 and is in direct competition with DDB2 for binding to DDB1. Hence, HBx-mediated cell death can be relieved by increased levels of DDB2, an effect that is not observed with a naturally occurring mutant of DDB2 that lacks DDB1-binding activity. These findings indicate that HBx acts through a pathway that involves a DDB2-independent nuclear function of DDB1 and that this activity will depend on the relative concentration of DDB1 and DDB2 in cells.
Bontron
Séverine
S
Department of Genetics and Microbiology, University Medical Centre, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland.
Lin-Marq
Nathalie
N
Strubin
Michel
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006511:Hepatitis B Antigens / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D054334:Viral Regulatory and Accessory Proteins
C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D006511:Hepatitis B Antigens; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein