Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex.
Mammalian hepatitis B viruses encode an essential regulatory protein, termed X, which may also be implicated in liver cancer development associated with chronic infection. X protein, also referred to as HBx in human virus and WHx in woodchuck virus, has been reported to bind to a number of cellular proteins, including the DDB1 subunit of the damaged DNA-binding (DDB) complex. Our previous work provided genetic evidence for the importance of WHx-DDB1 interaction in both the activity of the X protein and establishment of viral infection in woodchucks. In the present study, a direct action of DDB1 on the X protein is documented. Physical interaction between the two proteins leads to an increase in X protein stability. This effect results from protection of the viral protein from proteasome-mediated degradation. Protection of WHx is overcome in the presence DDB2, the second subunit of the DDB heterodimer. In keeping with observations reported for HBx, DDB2 was found to directly bind to WHx. Nonetheless, the counteracting effect of DDB2 on X stabilization requires DDB2-DDB1 interaction. Taken together, these findings substantiate the physical and functional connection between the X protein and the DDB1-DDB2 heterodimer, leading to the regulation of the pool of the viral protein.
Bergametti
Françoise
F
Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
Sitterlin
Delphine
D
Transy
Catherine
C
D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D015967:Gene Expression Regulation, Viral; D006207:Half-Life; D006515:Hepatitis B virus / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex