title: High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression.
abstract: Persistent infections with human papillomavirus type 16 (HPV16), HPV18, or HPV31 are necessary for the development of cervical cancer, implying that HPVs have evolved immunoevasive mechanisms. Recent global transcriptome analyses indicated that these HPV types downregulate the constitutive expression of interferon (IFN)-stimulated genes (ISGs), but the underlying mechanism is not well understood. Comparative analyses of ISG transcription in keratinocytes with complete HPV16, -18, and -31 genomes revealed that antiviral genes (IFIT1 and MX1), genes involved in IFN signaling (STAT1), proapoptotic genes (TRAIL and XAF1), and pathogen recognition receptors (TLR3, RIG-I, and MDA5) are inhibited to similar extents by HPV16, -18, and -31. The lower expression of pathogen receptors in HPV-positive cells correlated with a greatly impaired induction of IFN-β and also of IFN-λ1, -2, and -3 upon receptor stimulation. IFN-κ is constitutively expressed in normal keratinocytes and is strongly repressed by HPV16, -18, and -31. ISGs downregulated in HPV-positive cells can be reactivated by IFN-κ expression. The viral E6 and E7 oncogenes are sufficient for IFN-κ repression, with E6 being mainly responsible. E6 inhibits IFN-κ transcription independently from binding to PDZ proteins. IFN-κ expression can be activated in only one cell line by E6AP knockdown but can be activated in all tested HPV-positive cells by addition of a DNA methyltransferase inhibitor, suggesting that HPVs modulate DNA methylation. Taken together, these results suggest that carcinogenic HPVs target IFN-κ by different pathways in keratinocytes to inhibit both antiviral ISGs and pathogen recognition receptors, which in turn reduces the expression of inducible IFNs.
authors.affiliation: University Hospital Tuebingen, Institute for Medical Virology and Epidemiology of Viral Diseases, Division of Experimental Virology, Elfriede-Aulhorn-Str. 6, D72076 Tuebingen, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Reiser
authors.forename: José
authors.initials: J
authors.lastname: Hurst
authors.forename: Maike
authors.initials: M
authors.lastname: Voges
authors.forename: Peter
authors.initials: P
authors.lastname: Krauss
authors.forename: Peter
authors.initials: P
authors.lastname: Münch
authors.forename: Thomas
authors.initials: T
authors.lastname: Iftner
authors.forename: Frank
authors.initials: F
authors.lastname: Stubenrauch
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D015603:Keratinocytes / Q000276:immunology / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000276:immunology* / Q000472:pathogenicity; D014158:Transcription, Genetic
chemical_list: D007370:Interferon Type I; D009856:Oncogene Proteins, Viral; C439669:interferon kappa