1. Loss of the HPV-Infection Resistance EVER2 Protein Impairs NF-κB Signaling Pathways in Keratinocytes
- Author
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Pierre-Henri Commere, Delphine Guillemot, Christian Pons, Michel Favre, Françoise Vuillier, Guillaume Gaud, Génétique, Papillomavirus et Cancer Humain, Institut Pasteur [Paris] (IP), Cytométrie (Plate-forme), This work was supported by grants from the ANR (contract no 02601), ARC (contract no A09/1/5031) and the Ligue Nationale Contre le Cancer (contract no RS07/75-75) and by a donation from ODYSSE RE Holdings Corp. G. Gaud was supported by an ANR fellowship (contract no 02601)., and Institut Pasteur [Paris]
- Subjects
Keratinocytes ,MESH: Signal Transduction ,Viral Diseases ,TRAF2 ,Skin Neoplasms ,Tumor Physiology ,MESH: TNF Receptor-Associated Factor 2 ,MESH: NF-kappa B ,MESH: Microscopy, Fluorescence ,MESH: Papillomavirus Infections ,Basic Cancer Research ,Phosphorylation ,Skin Tumors ,Disease Resistance ,Multidisciplinary ,MESH: Real-Time Polymerase Chain Reaction ,Cancer Risk Factors ,NF-kappa B ,Obstetrics and Gynecology ,MESH: Keratinocytes ,I-kappa B Kinase ,3. Good health ,Infectious Diseases ,medicine.anatomical_structure ,Oncology ,Medicine ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,MESH: Protein Kinase C-alpha ,MESH: Membrane Proteins ,Signal transduction ,Keratinocyte ,Signal Transduction ,Research Article ,Tumor Immunology ,MESH: DNA Primers ,Human Papillomavirus Infection ,Protein Kinase C-alpha ,Science ,Urology ,Blotting, Western ,Immunology ,Genetic Causes of Cancer ,Sexually Transmitted Diseases ,MESH: Disease Resistance ,Dermatology ,Biology ,Real-Time Polymerase Chain Reaction ,Downregulation and upregulation ,Genetic Mutation ,Genetics ,medicine ,Humans ,Immunoprecipitation ,MESH: Blotting, Western ,MESH: I-kappa B Kinase ,DNA Primers ,MESH: Humans ,MESH: Phosphorylation ,Genitourinary Infections ,MESH: Immunoprecipitation ,Papillomavirus Infections ,Membrane Proteins ,Cancers and Neoplasms ,Epidermodysplasia verruciformis ,Immunologic Subspecialties ,TNF Receptor-Associated Factor 2 ,medicine.disease ,NFKB1 ,Molecular biology ,Microscopy, Fluorescence ,Cancer research ,Clinical Immunology - Abstract
International audience; 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.
- Published
- 2014
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