title: HPV16 E5 deregulates the autophagic process in human keratinocytes.
abstract: Autophagy plays key roles during host defense against pathogens, but viruses have evolved strategies to block the process or to exploit it for replication and successful infection. The E5 oncoprotein of human papillomavirus type 16 (HPV16 E5) perturbs epithelial homeostasis down-regulating the expression of the keratinocyte growth factor receptor (KGFR/FGFR2b), whose signaling induces autophagy. Here we investigated the possible effects of 16E5 on autophagy in human keratinocytes expressing the viral protein. The 16E5 presence strongly inhibited the autophagic process, while forced expression and activation of KGFR counteracted this effect, demonstrating that the viral protein and the receptor exert opposite and interplaying roles not only on epithelial differentiation, but also in the control of autophagy. In W12 cells, silencing of the 16E5 gene in the context of the viral full length genome confirmed its role on autophagy inhibition. Finally, molecular approaches showed that the viral protein interferes with the transcriptional regulation of autophagy also through the impairment of p53 function, indicating that 16E5 uses parallel mechanisms for autophagy impairment. Overall our results further support the hypothesis that a transcriptional crosstalk among 16E5 and KGFR might be the crucial molecular driver of epithelial deregulation during early steps of HPV infection and transformation.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nanni
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Azienda Ospedaliera S. Andrea, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Raffa
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy.|Azienda Ospedaliera S. Andrea, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
mesh_terms: D001343:Autophagy / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D000086082:Viroporin Proteins
chemical_list: D009856:Oncogene Proteins, Viral; D051497:Receptor, Fibroblast Growth Factor, Type 2; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
keywords: FGFR2b; HPV; KGF/FGF7; KGFR; autophagy
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