HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses

Morgan, Huw J., Olivero, Carlotta ORCID: https://orcid.org/0000-0002-8961-6703, Shorning, Boris Y., Gibbs, Alex, Phillips, Alexandra L., Ananthan, Lokapriya, Lim, Annabelle Xiao Hui, Martuscelli, Licia, Borgogna, Cinzia, De Andrea, Marco, Hufbauer, Martin, Goodwin, Richard G., Akgül, Baki, Gariglio, Marisa and Patel, Girish K. 2024. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses. JCI Insight 9 (15) , e177898. 10.1172/jci.insight.177898

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Abstract

Despite epidermal turnover, the skin is host to a complex array of microbes, including viruses, such as HPV, which must infect and manipulate skin keratinocyte stem cells (KSCs) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission. Within Lrig1+ KSCs specifically, HPV8 E6 bound intracellular p300 to phosphorylate the STAT3 transcriptional regulatory node. This induced ΔNp63 expression, resulting in KSC expansion into the overlying epidermis. HPV8 was associated with 70% of human actinic keratoses. Together, these results define the “hit-and-run” mechanism for HPV8 in human actinic keratosis as an expansion of KSCs, which lack melanosome protection and are thus susceptible to sun light–induced malignant transformation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	1 August 2024
Date of Acceptance:	25 June 2024
Last Modified:	13 Aug 2024 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/171092

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