Borna disease virus phosphoprotein represses p53-mediated transcriptional activity by interference with HMGB1.
Borna disease virus (BDV) is a noncytolytic, neurotropic RNA virus that has a broad host range in warm-blooded animals, probably including humans. Recently, it was demonstrated that a 24-kDa phosphoprotein (P) of BDV directly binds to a multifunctional protein, amphoterin-HMGB1, and inhibits its function in cultured neural cells (W. Kamitani, Y. Shoya, T. Kobayashi, M. Watanabe, B. J. Lee, G. Zhang, K. Tomonaga, and K. Ikuta, J. Virol. 75:8742-8751, 2001). This observation suggested that expression of BDV P may cause deleterious effects in cellular functions by interference with HMGB1. In this study, we further investigated the significance of the binding between P and HMGB1. We demonstrated that P directly binds to the A-box domain on HMGB1, which is also responsible for interaction with a tumor suppression factor, p53. Recent works have demonstrated that binding between HMGB1 and p53 enhances p53-mediated transcriptional activity. Thus, we examined whether BDV P affects the transcriptional activity of p53 by interference with HMGB1. Mammalian two-hybrid analysis revealed that p53 and P competitively interfere with the binding of each protein to HMGB1 in a p53-deficient cell line, NCI-H1299. In addition, P was able to significantly decrease p53-mediated transcriptional activation of the cyclin G promoter. Furthermore, we showed that activation of p21(waf1) expression was repressed in cyclosporine-treated BDV-infected cells, as well as p53-transduced NCI-H1299 cells. These results suggested that BDV P may be a unique inhibitor of p53 activity via binding to HMGB1.
Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Guoqi
G
Zhang
Takeshi
T
Kobayashi
Wataru
W
Kamitani
Satoshi
S
Komoto
Makiko
M
Yamashita
Satoko
S
Baba
Hideyuki
H
Yanai
Kazuyoshi
K
Ikuta
Keizo
K
Tomonaga
D000818:Animals; D001667:Binding, Competitive; D001891:Borna disease virus / Q000502:physiology*; D045744:Cell Line, Tumor; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000378:metabolism; D024243:HMGB1 Protein / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology*
C534702:CCNG1 protein, human; C534704:Ccng1 protein, rat; C493958:Cdkn1a protein, rat; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D024243:HMGB1 Protein; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C084757:p24 protein, Borna disease virus; D004247:DNA