Human papillomavirus type 8 interferes with a novel C/EBPβ-mediated mechanism of keratinocyte CCL20 chemokine expression and Langerhans cell migration.
Infection with genus beta human papillomaviruses (HPV) is implicated in the development of non-melanoma skin cancer. This was first evidenced for HPV5 and 8 in patients with epidermodysplasia verruciformis (EV), a genetic skin disease. So far, it has been unknown how these viruses overcome cutaneous immune control allowing their persistence in lesional epidermis of these patients. Here we demonstrate that Langerhans cells, essential for skin immunosurveillance, are strongly reduced in HPV8-positive lesional epidermis from EV patients. Interestingly, the same lesions were largely devoid of the important Langerhans cells chemoattractant protein CCL20. Applying bioinformatic tools, chromatin immunoprecipitation assays and functional studies we identified the differentiation-associated transcription factor CCAAT/enhancer binding protein β (C/EBPβ) as a critical regulator of CCL20 gene expression in normal human keratinocytes. The physiological relevance of this finding is supported by our in vivo studies showing that the expression patterns of CCL20 and nuclear C/EBPβ converge spatially in the most differentiated layers of human epidermis. Our analyses further identified C/EBPβ as a novel target of the HPV8 E7 oncoprotein, which co-localizes with C/EBPβ in the nucleus, co-precipitates with it and interferes with its binding to the CCL20 promoter in vivo. As a consequence, the HPV8 E7 but not E6 oncoprotein suppressed C/EBPβ-inducible and constitutive CCL20 gene expression as well as Langerhans cell migration. In conclusion, our study unraveled a novel molecular mechanism central to cutaneous host defense. Interference of the HPV8 E7 oncoprotein with this regulatory pathway allows the virus to disrupt the immune barrier, a major prerequisite for its epithelial persistence and procarcinogenic activity.
Institute of Virology and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Tanya
T
Sperling
Monika
M
Ołdak
Barbara
B
Walch-Rückheim
Claudia
C
Wickenhauser
John
J
Doorbar
Herbert
H
Pfister
Magdalena
M
Malejczyk
Sławomir
S
Majewski
Andrew C
AC
Keates
Sigrun
S
Smola
D052686:Betapapillomavirus / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004817:Epidermis / Q000378:metabolism / Q000821:virology; D004819:Epidermodysplasia Verruciformis / Q000821:virology; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D007801:Langerhans Cells / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology*; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000821:virology*
D022782:CCAAT-Enhancer-Binding Protein-beta; C108355:CCL20 protein, human; C545012:CEBPB protein, human; D054418:Chemokine CCL20; D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral