Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins

被引:14
作者
Aoyagi, M
Higashino, F
Yasuda, M
Takahashi, A
Sawada, Y
Totsuka, Y
Kohgo, T
Sano, H
Kobayashi, M
Shindoh, M
机构
[1] Hokkaido Univ, Grad Sch Dent Med, Dept Oral Pathobiol Sci, Kita Ku, Sapporo, Hokkaido 0608586, Japan
[2] Hokkaido Univ, Grad Sch Dent Med, Dept Oral Hlth Sci, Kita Ku, Sapporo, Hokkaido 0608586, Japan
[3] Hokkaido Inst Publ Hlth, Dept Biol, Sapporo, Hokkaido 0600819, Japan
[4] Hokkaido Univ, Sch Med, Inst Med Genet, Div Canc Pathobiol, Sapporo, Hokkaido 0608638, Japan
关键词
E4orf6; adenovirus; nuclear export; BH-3 only protein; BNIP3; Bik;
D O I
10.1038/sj.onc.1206743
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The adenovirus E4orf6 is a viral oncoprotein known to cooperate with the E1A gene product in transforming primary murine cells. It has been shown to inhibit the apoptotic activities of p53 and p73 through direct binding to these proteins. Here, we demonstrate that the adenovirus E4orf6 protein inhibits apoptosis mediated by BNIP3 and Bik, which are BH3-only proteins of the Bcl-2 family. This activity was not mediated by p53 and p73 because E4orf6 had the same effect on the apoptosis in Saos-2 cells that do not express p53-related genes. It was also ascertained that E4orf6 could change the mitochondrial localization of BNIP3 and Bik. A mutant lacking the nuclear export signal of E4orf6 failed to inhibit apoptosis and to translocate BNIP3 protein from the mitochondria. Moreover, it was also established that E4orf6 was able to interact with BNIP3 and Bik. In BNIP3 protein, the region required for the interaction included the transmembrane domain, which is required for the localization of BNIP3 to the mitochondria. These results suggest that E4orf6 is exported from the nucleus to the cytoplasm, enabling it to interact with BH3-only proteins, eventually leading to the inhibition of apoptotic activity.
引用
收藏
页码:6919 / 6927
页数:9
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