Human papillomavirus type 8 E2 protein unravels JunB/Fra-1 as an activator of the beta4-integrin gene in human keratinocytes.
The papillomavirus life cycle parallels keratinocyte differentiation in stratifying epithelia. We have previously shown that the human papillomavirus type 8 (HPV8) E2 protein downregulates beta4-integrin expression in normal human keratinocytes, which may trigger subsequent differentiation steps. Here, we demonstrate that the DNA binding domain of HPV8 E2 is sufficient to displace a cellular factor from the beta4-integrin promoter. We identified the E2-displaceable factor as activator protein 1 (AP-1), a heteromeric transcription factor with differentiation-specific expression in the epithelium. beta4-Integrin-positive epithelial cells displayed strong AP-1 binding activity. Both AP-1 binding activity and beta4-integrin expression were coregulated during keratinocyte differentiation suggesting the involvement of AP-1 in beta4-integrin expression. In normal human keratinocytes the AP-1 complex was composed of JunB and Fra-1 subunits. Chromatin immunoprecipitation assays confirmed that JunB/Fra-1 proteins interact in vivo with the beta4-integrin promoter and that JunB/Fra-1 promoter occupancy is reduced during keratinocyte differentiation as well as in HPV8 E2 positive keratinocytes. Ectopic expression of the tethered JunB/Fra-1 heterodimer in normal human keratinocytes activated the beta4-integrin promoter, while coexpression of HPV8 E2 reverted the JunB/Fra-1 effect. In summary, we identified a novel mechanism of human beta4-integrin regulation that is specifically targeted by the HPV8 E2 protein mimicking transcriptional conditions of differentiation. This may explain the early steps of how HPV8 commits its host cells to the differentiation process required for the viral life cycle.
Oldak
Monika
M
Institute of Virology, Saarland University, Kirrbergerstrasse, Building 47, 66421 Homburg/Saar, Germany.
Maksym
Radoslaw B
RB
Sperling
Tanya
T
Yaniv
Moshe
M
Smola
Hans
H
Pfister
Herbert J
HJ
Malejczyk
Jacek
J
Smola
Sigrun
S
D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D019281:Dimerization; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics*; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D000099169:Fos-Related Antigen 1
D017931:DNA Primers; D039663:Integrin beta4; D009856:Oncogene Proteins, Viral; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D000099169:Fos-Related Antigen 1; C468298:oncogene protein E2, Human papillomavirus type 8