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.
Highlights
Autophagy is a highly regulated “self-digestion” pathway [1], which is enhanced by cellular stresses, such as nutrient starvation or hypoxia [2], and plays a crucial role during host defense, permitting pathogens detection and their rapid lysosomal degradation [3]
Since we have recently demonstrated that 16E5 down-regulates KGFR [12, 13], whose ligand-specific activation triggers autophagy in keratinocytes [16], here we analyzed the effects of 16E5 ectopic expression on KGF-triggered autophagy in the human keratinocyte HaCaT cell line, spontaneously immortalized from a primary culture of keratinocytes [17]
In order to verify if the ability of 16E5 to transcriptionally regulate autophagy is a general phenomenon, we examined the expression of the autophagic genes in primary human keratinocytes transiently transfected with 16E5 (HKs E5) or with the pCI-neo empty vector (HKs pCI-neo) as control
Summary
Autophagy is a highly regulated “self-digestion” pathway [1], which is enhanced by cellular stresses, such as nutrient starvation or hypoxia [2], and plays a crucial role during host defense, permitting pathogens detection and their rapid lysosomal degradation [3]. The depletion of all the HPV16 early proteins resulted in a strong increase of autophagy in infected cervical keratinocytes [9]. Even if this latter evidence has suggested a possible intriguing function for the entire “early protein group” of HPV16 in inhibiting the autophagy onset and in determining postinfection virus survival, the single contribution of each of the early proteins and the possible molecular mechanisms involved remain to be clarified
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
