E2 proteins of high risk human papillomaviruses down-modulate STING and IFN-κ transcription in keratinocytes

PLoS One. 2014 Mar 10;9(3):e91473. doi: 10.1371/journal.pone.0091473. eCollection 2014.

Abstract

In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation* / drug effects
  • Female
  • Gene Regulatory Networks
  • Genome, Human / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Interferon Type I / genetics*
  • Interferon Type I / metabolism
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Oncogene Proteins, Viral / chemistry
  • Oncogene Proteins, Viral / metabolism*
  • Poly I-C / pharmacology
  • Protein Structure, Tertiary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Recombination, Genetic
  • Transcription, Genetic* / drug effects
  • Transduction, Genetic

Substances

  • DNA-Binding Proteins
  • E2 protein, Human papillomavirus type 16
  • Interferon Type I
  • Membrane Proteins
  • Oncogene Proteins, Viral
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • STING protein, human
  • interferon kappa
  • oncogene protein E2, Human papillomavirus type 18
  • Green Fluorescent Proteins
  • Poly I-C

Grant support

This work was supported by grants from the Faculty of Medicine (I54328), Khon Kaen University (551602, 564102 and 573002) and the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (#PHD/0213/2550) to student’s NS and advisor’s TE is acknowledged. The funders had no role in study design, data collection, data analysis, preparation of manuscript and decision to publish.