Phospholipidation of nuclear proteins by the human papillomavirus E6 oncoprotein: implication in carcinogenesis
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Benjamin Marx1, Martin Hufbauer1, Paola Zigrino2, Slawomir Majewski3, Birgid Markiefka4, Timo Sachsenheimer5, Britta Brügger5 and Baki Akgül1
1Institute of Virology, University of Cologne, Cologne, Germany
2Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
3Department of Dermatology and Venereology, Medical University of Warsaw, Warsaw, Poland
4Institute of Pathology, University Hospital Cologne, Cologne, Germany
5Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany
Baki Akgül, email: [email protected]
Keywords: human papillomavirus; E6 oncoprotein; phosphatidylinositides; nuclear phosphatidylinositol-4,5-bisphosphate; skin cancer
Received: June 30, 2018 Accepted: September 06, 2018 Published: September 25, 2018
Phospholipids regulate numerous cellular functions and their deregulation is known to be associated with cancer development. Here, we show for the first time that expression of the E6 oncoprotein of human papillomavirus type 8 (HPV8) leads to a profound increase in nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) lipid levels in monolayer cultures, that led to an aberrant phospholipidation of cellular proteins. Elevated PI(4,5)P2 levels in organotypic skin cultures, skin tumors of K14-HPV8-E6 transgenic mice as well as HPV8 positive skin carcinomas highly suggest a decisive role of PI(4,5)P2 in HPV associated squamous-cell-carcinoma development. Furthermore, mass-spectrometric analysis confirmed an increase of PI(4,5)P2, which was characterized by a shift in the distribution of lipid species. PI(4,5)P2 upregulation was independent of E6 interference with MAML1. However, E6 does interfere with the PI(4,5)P2 metabolic pathway by upregulation of phosphatidylinositol-4-phosphate-5-kinase type I and phosphatidylinositol-5-phosphate 4-kinase type II as well as the binding to 5’-phosphatase OCRL and phosphatidylinositol. All of these mechanisms combined may contribute to PI(4,5)P2 elevation in E6 positive cells. The identification of CAND1 and SND1 – two proteins known to be involved in carcinogenic processes – were significantly stronger phospholipidized in the presence of E6. In conclusion we provide evidence that the modulation of the PI(4,5)P2 metabolism is a novel oncogenic mechanism relevant for HPV-induced carcinogenesis.
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