HPV E6 inhibits E6AP to regulate epithelial homeostasis by modulating keratinocyte differentiation commitment and YAP1 activation

Human papillomaviruses (HPV) typically cause chronic infections by modulating homeostasis of infected basal cell to ensure persistence. Using FUCCI and cell-cell competition assays, we established the role of two common viral targets of low-risk and high-risk E6 proteins, E6AP and NHERF1, on the key components of epithelial homeostasis: cell density, proliferation, commitment to differentiation and basal layer delamination. Importantly, we demonstrate that deletion of E6AP in keratinocytes delayed the onset of differentiation and the abundance of E6AP is reduced in HPV-infected tissue. RNA sequencing revealed similar transcriptional profiles of E6-expressing cells and E6AP-/- cells. Amongst the pathways identified, YAP target genes were activated by either E6 expression or E6AP depletion. This is confirmed by the analysis of YAP expression pattern in both monolayer cell culture and HPV-infected lesions. As the conserved binding partner of Alpha group HPV E6 proteins, the precise role of E6AP in modulating keratinocyte phenotype and associated signalling pathways have not been defined. Our study suggests a model which explains the preserved functions of low-risk and high-risk Alpha E6 in epithelial homeostasis by inhibiting E6AP’s activity, hence leading to alteration of multiple downstream pathways including YAP activation. Potential treatments can thus be developed.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Yin, Wen

Advisor dc:contributor.advisor

• Doorbar, John

• E6
• E6AP
• HPV
• keratinocyte
• YAP

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/19500433-4543-4eef-986e-33bfea201596/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.102199

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/358711