The human papillomavirus type 8 E2 protein suppresses beta4-integrin expression in primary human keratinocytes.
Human papillomaviruses (HPVs) infect keratinocytes of skin and mucosa. Homeostasis of these constantly renewing, stratified epithelia is maintained by balanced keratinocyte proliferation and terminal differentiation. Instructions from the extracellular matrix engaging integrins strongly regulate these keratinocyte functions. The papillomavirus life cycle parallels the differentiation program of stratified epithelia, and viral progeny is produced only in terminally differentiating keratinocytes. Whereas papillomavirus oncoproteins can inhibit keratinocyte differentiation, the viral transcription factor E2 seems to counterbalance the impact of oncoproteins. In this study we show that high expression of HPV type 8 (HPV8) E2 in cultured primary keratinocytes leads to strong down-regulation of beta4-integrin expression levels, partial reduction of beta1-integrin, and detachment of transfected keratinocytes from underlying structures. Unlike HPV18 E2-expressing keratinocytes, HPV8 E2 transfectants did not primarily undergo apoptosis. HPV8 E2 partially suppressed beta4-integrin promoter activity by binding to a specific E2 binding site leading to displacement of at least one cellular DNA binding factor. To our knowledge, we show for the first time that specific E2 binding contributes to regulation of a cellular promoter. In vivo, decreased beta4-integrin expression is associated with detachment of keratinocytes from the underlying basement membrane and their egress from the basal to suprabasal layers. In papillomavirus disease, beta4-integrin down-regulation in keratinocytes with higher E2 expression may push virally infected cells into the transit-amplifying compartment and ensure their commitment to the differentiation process required for virus replication.
Oldak
Monika
M
Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany.
Smola
Hans
H
Aumailley
Monique
M
Rivero
Francisco
F
Pfister
Herbert
H
Smola-Hess
Sigrun
S
D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D039663:Integrin beta4 / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology*; D008856:Microscopy, Fluorescence; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D027383:Papillomaviridae / Q000472:pathogenicity*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000502:physiology*
D004268:DNA-Binding Proteins; D019012:Integrin beta1; D039663:Integrin beta4; D009856:Oncogene Proteins, Viral; D015534:Trans-Activators; C468298:oncogene protein E2, Human papillomavirus type 8