Dataset Information

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

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-? 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-? 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-? and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-? were further determined in clinical specimens by real time PCR. STING and IFN-? 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-? transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

SUBMITTER: Sunthamala N

PROVIDER: S-EPMC3948877 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Sunthamala Nuchsupha N Thierry Francoise F Teissier Sebastien S Pientong Chamsai C Kongyingyoes Bunkerd B Tangsiriwatthana Thumwadee T Sangkomkamhang Ussanee U Ekalaksananan Tipaya T

PloS one 20140310 3

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 inve ...[more]

PMID: 24614210

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Project description: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-?), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-? has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-? by hr-HPV raises the possibility that IFN-? has anti-HPV activity. Using doxycycline-inducible IFN-? expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-? 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-? expression. This was also observed with recombinant IFN-?, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-?-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-? 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-?. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-? to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity.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-?, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-? rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV.

Dataset Information

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

Publications

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

Similar Datasets

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