title: Loss of the HPV-infection resistance EVER2 protein impairs NF-κB signaling pathways in keratinocytes.
abstract: Homozygous mutations in EVER genes cause epidermodysplasia verruciformis (EV), characterized by an immune defect and the development of skin cancers associated with β-human papillomavirus (HPV) infections. The effects of EVER protein loss on the keratinocyte immune response remain unknown. We show here that EVER2 plays a critical role in the interplay between the NF-κB and JNK/AP-1 signaling pathways. EVER2-deficient cells overproduce IL-6 following the upregulation of JNK activation. They respond poorly to phorbol ester and TNF via the NF-κB pathway. They have lower levels of IKKα subunit, potentially accounting for impairments of p100 processing and the alternative NF-κB pathway. The loss of EVER2 is associated with an unusual TRAF protein profile. We demonstrate that EVER2 deficiency sustains TRAF2 ubiquitination and decreases the pool of TRAF2 available in the detergent-soluble fraction of the cell. Finally, we demonstrate that EVER2 loss induces constitutive PKCα-dependent c-jun phosphorylation and facilitates activation of the HPV5 long control region through a JNK-dependent pathway. These findings indicate that defects of the EVER2 gene may create an environment conducive to HPV replication and the persistence of lesions with the potential to develop into skin cancer.
authors.affiliation: Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Vuillier
authors.affiliation: Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gaud
authors.affiliation: Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Guillemot
authors.affiliation: Plateforme de cytométrie en flux, Institut Pasteur, Paris, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Commere
authors.affiliation: Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Pons
authors.affiliation: Unité de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Favre
mesh_terms: D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D060467:Disease Resistance / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D008565:Membrane Proteins; D016328:NF-kappa B; C470315:TMC8 protein, human; D047992:TNF Receptor-Associated Factor 2; D051550:I-kappa B Kinase; D051571:Protein Kinase C-alpha