HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses
Huw J. Morgan, Carlotta Olivero, Boris Y. Shorning, Alex Gibbs, Alexandra L. Phillips, Lokapriya Ananthan, Annabelle Xiao Hui Lim, Licia Martuscelli, Cinzia Borgogna, Marco De Andrea, Martin Hufbauer, Richard Goodwin, Baki Akgül, Marisa Gariglio, Girish K. Patel
Huw J. Morgan, Carlotta Olivero, Boris Y. Shorning, Alex Gibbs, Alexandra L. Phillips, Lokapriya Ananthan, Annabelle Xiao Hui Lim, Licia Martuscelli, Cinzia Borgogna, Marco De Andrea, Martin Hufbauer, Richard Goodwin, Baki Akgül, Marisa Gariglio, Girish K. Patel
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Research Article Cell biology Stem cells

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

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.

Authors

Huw J. Morgan, Carlotta Olivero, Boris Y. Shorning, Alex Gibbs, Alexandra L. Phillips, Lokapriya Ananthan, Annabelle Xiao Hui Lim, Licia Martuscelli, Cinzia Borgogna, Marco De Andrea, Martin Hufbauer, Richard Goodwin, Baki Akgül, Marisa Gariglio, Girish K. Patel

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Figure 6

YAP a cotranscription factor for STAT3 and

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YAP a cotranscription factor for STAT3 and ΔNp63. (A and B) pSTAT3 Y705,...
ΔNp63. (A and B) pSTAT3 Y705, ΔNp63, and YAP immunoblot, with TATA-box binding protein endogenous control, of nuclear extracts from Lrig1+ flow-sorted WT and HPV8-E6tg mouse keratinocytes (A) and HPV8 E6– and vector control–transduced HaCaT keratinocytes (B) (n = 3 per genotype/cell line). (C) pSTAT3 Y705, total STAT3 and YAP immunoblot, with GAPDH endogenous loading control, of HPV8 E6–transduced HaCaT keratinocytes treated with scrambled control and YAP targeting siRNA (n = 3). (D) Immunofluorescence labeling of HPV8 E6– and vector control–transduced HaCaT keratinocytes cultured at low (~50%) and high (~90%) confluency for YAP (green), pSTAT3 Y705 (red), and ΔNp63 (yellow), with quantification of nuclear mean fluorescent intensity (n = 82 cells total quantified over 3 independent experiments). Scale bar: 40 μm. (E) Immunoblot of YAP immunoprecipitated nuclear protein from vector control– and HPV8 E6–transduced HaCaT cells probed for STAT3 and ΔNp63 (n = 3). (F) Proliferation of HPV8 E6– and vector control–transduced HaCaT keratinocytes assessed by 24 hours of BrdU incorporation following treatment with YAP targeting siRNA (n = 3). See also Supplemental Figure 5. Statistical tests included (A–E) 2-tailed Student’s t test and (F) 1-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001.