Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism

• Published in: PloS one 2013-09, Vol.8 (9), p.e75625
• Main Authors: Lai, Deborah, Tan, Chye Ling, Gunaratne, Jayantha, Quek, Ling Shih, Nei, Wenlong, Thierry, Françoise, Bellanger, Sophie
• Format: Article
• Language: English
• Subjects: Analysis; Apoptosis; Apoptosis - physiology; Biology; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Nucleus - virology; Cristae; Cytochrome; Cytoplasm; Cytoplasm - metabolism; Cytoplasm - virology; Deoxyribonucleic acid; DNA; E2 protein; Electron microscopy; Electron transport; Genomes; Glycolysis; Glycolysis - physiology; Hepatitis; Human papillomavirus; Human papillomavirus 18 - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Infections; Localization; Mass spectrometry; Mass spectroscopy; Membranes; Metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - virology; Mitochondrial Membranes - metabolism; Mitochondrial Membranes - virology; Nuclei; Nuclei (cytology); Oncogene Proteins, Viral - metabolism; Papillomavirus infections; Physiological aspects; Protein turnover; Proteins; Reactive Oxygen Species - metabolism; Respiration; Risk; Science; Spacecraft components; Viral infections; Viral Proteins - metabolism; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075625

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.