Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins
Autor: | Christina Habiger, Thomas Iftner, Frank Stubenrauch, Michael J. Walter, Günter Jäger |
---|---|
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Transcription Genetic Immunology Biology Virus Replication Autoantigens Microbiology Transcriptome 03 medical and health sciences Transcription (biology) RNA interference Interferon Cell Line Tumor Virology medicine Humans Human papillomavirus 31 Gene virus diseases Antigens Nuclear Epithelial Cells Virus-Cell Interactions Cell biology 030104 developmental biology Viral replication Cell culture Insect Science Host-Pathogen Interactions Interferon Type I Interferon type I medicine.drug |
Zdroj: | Journal of Virology. 90:694-704 |
ISSN: | 1098-5514 0022-538X |
DOI: | 10.1128/jvi.02137-15 |
Popis: | High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-κ), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-β has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-κ by hr-HPV raises the possibility that IFN-κ has anti-HPV activity. Using doxycycline-inducible IFN-κ expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-κ inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited at 4 to 6 h after IFN-κ expression. This was also observed with recombinant IFN-β, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-κ-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-κ acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNA interference (RNAi) and cotransfection experiments indicated that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-κ. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-κ to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity. IMPORTANCE High-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN-κ, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-κ rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV. |
Databáze: | OpenAIRE |
Externí odkaz: |