Oncotarget

Research Papers:

HPV16 E5 deregulates the autophagic process in human keratinocytes

Francesca Belleudi _, Monica Nanni, Salvatore Raffa and Maria Rosaria Torrisi

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Oncotarget. 2015; 6:9370-9386. https://doi.org/10.18632/oncotarget.3326

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Abstract

Francesca Belleudi1, Monica Nanni1, Salvatore Raffa1,2, Maria Rosaria Torrisi1,2

1Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy

2Azienda Ospedaliera S. Andrea, Rome, Italy

Correspondence to:

Francesca Belleudi, e-mail: francesca.belleudi@uniroma1.it

Maria Rosaria Torrisi, e-mail: mara.torrisi@uniroma1.it

Keywords: HPV, KGF/FGF7, KGFR, FGFR2b, autophagy

Received: December 22, 2014     Accepted: February 09, 2015     Published: March 19, 2015

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.


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