Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins
Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins
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DOI：
10.1038/sj.onc.1206743
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发表时间：
2003-10-09
期刊：
影响因子：
8
通讯作者：
Shindoh, M
中科院分区：
文献类型：
--
作者：
Aoyagi, M;Higashino, F;Shindoh, M
腺病毒E4 orf 6是一种已知与E1 A基因产物协同转化原代鼠细胞的病毒癌蛋白。已经显示通过直接结合p53和p73蛋白来抑制这些蛋白的凋亡活性。在这里，我们证明了腺病毒E4 orf 6蛋白抑制由BNIP 3和Bik介导的细胞凋亡，BNIP 3和Bik是Bcl-2家族的仅BH 3蛋白。这种活性不是由p53和p73介导的，因为E4 orf 6对不表达p53相关基因的Saos-2细胞的凋亡具有相同的作用。E4 orf 6可以改变BNIP 3和Bik的线粒体定位。缺乏E4 orf 6的核输出信号的突变体不能抑制细胞凋亡和从线粒体易位BNIP 3蛋白。此外，还确定E4 orf 6能够与BNIP 3和Bik相互作用。在BNIP 3蛋白中，相互作用所需的区域包括跨膜结构域，这是BNIP 3定位于线粒体所必需的。这些结果表明，E4 orf 6从细胞核输出到细胞质，使其能够与仅BH 3蛋白相互作用，最终导致凋亡活性的抑制。
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.