Papillomavirus Regulation and Cancer, Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.
PLoS One. 2013 Sep 24;8(9):e75625. doi: 10.1371/journal.pone.0075625. eCollection 2013.
Papillomavirus E2 proteins are predominantly retained in the nuclei of infected cells, but oncogenic (high-risk) HPV-18 and 16 E2 can shuttle between the host nucleus and cytoplasm. We show here that cytoplasmic HPV-18 E2 localizes to mitochondrial membranes, and independent mass spectrometry analyses of the E2 interactome revealed association to the inner mitochondrial membrane including components of the respiratory chain. Mitochondrial E2 association modifies the cristae morphology when analyzed by electron microscopy and increases production of mitochondrial ROS. This ROS release does not induce apoptosis, but instead correlates with stabilization of HIF-1α and increased glycolysis. These mitochondrial functions are not shared by the non-oncogenic (low-risk) HPV-6 E2 protein, suggesting that modification of cellular metabolism by high-risk HPV E2 proteins could play a role in carcinogenesis by inducing the Warburg effect.
乳头瘤病毒 E2 蛋白主要保留在受感染细胞的核内，但致癌（高危）HPV-18 和 16 E2 可以在宿主核和细胞质之间穿梭。我们在这里表明，细胞质 HPV-18 E2 定位于线粒体膜，并且对 E2 相互作用组的独立质谱分析显示与包括呼吸链成分在内的内线粒体膜相关联。当通过电子显微镜分析时，线粒体 E2 的关联会改变嵴的形态，并增加线粒体 ROS 的产生。这种 ROS 释放不会诱导细胞凋亡，而是与 HIF-1α 的稳定和糖酵解的增加相关。这些线粒体功能与非致癌（低危）HPV-6 E2 蛋白不同，这表明高危 HPV E2 蛋白对细胞代谢的修饰可能通过诱导沃伯格效应在致癌作用中发挥作用。
