DDB2 induces nuclear accumulation of the hepatitis B virus X protein independently of binding to DDB1.
The hepatitis B virus (HBV) X protein (HBx) is critical for the life cycle of the virus. HBx associates with several host cell proteins including the DDB1 subunit of the damaged-DNA binding protein DDB. Recent studies on the X protein encoded by the woodchuck hepadnavirus have provided correlative evidence indicating that the interaction with DDB1 is important for establishment of infection by the virus. In addition, the interaction with DDB1 has been implicated in the nuclear localization of HBx. Because the DDB2 subunit of DDB is required for the nuclear accumulation of DDB1, we investigated the role of DDB2 in the nuclear accumulation of HBx. Here we show that expression of DDB2 increases the nuclear levels of HBx. Several C-terminal deletion mutants of DDB2 that fail to bind DDB1 are able to associate with HBx, suggesting that DDB2 may associate with HBx independently of binding to DDB1. We also show that DDB2 enhances the nuclear accumulation of HBx independently of binding to DDB1, since a mutant that does not bind DDB1 is able to enhance the nuclear accumulation of HBx. HBV infection is associated with liver pathogenesis. We show that the nuclear levels of DDB1 and DDB2 are tightly regulated in hepatocytes. Studies with regenerating mouse liver indicate that during late G1 phase the nuclear levels of both subunits of DDB are transiently increased, followed by a sharp decrease in S phase. Taken together, these results suggest that DDB1 and DDB2 would participate in the nuclear functions of HBx effectively only during the late-G1 phase of the cell cycle.
Nag
A
A
Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Datta
A
A
Yoo
K
K
Bhattacharyya
D
D
Chakrabortty
A
A
Wang
X
X
Slagle
B L
BL
Costa
R H
RH
Raychaudhuri
P
P
D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D016193:G1 Phase; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D021122:Protein Subunits; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins
C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; D021122:Protein Subunits; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein