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Fig. 3 | Journal of Experimental & Clinical Cancer Research

Fig. 3

From: hrHPV E5 oncoprotein: immune evasion and related immunotherapies

Fig. 3

Interferon synthesis and signaling pathways. Interferons are crucial molecules for creating antiviral status. E5 stimulates IFN synthesis through activation of NF-κB signalling pathway and IRF-1 protein. (1) PRR/MAVS (Mitochondrial antiviral signaling) activates IKK that liberates NF-κB. (2) NF-κB, IRF-3 and ATF-2/c-Jun form a transcriptional complex that recruits the (3) CPB/P300 enhancer to IFN-β promoter. (4) This complex (along with IRF-1) binds to (5) particular DNA regions (PRDI, PRDII and PRDIV) which results in (6) IFN-β gene transcription. In IFN-independent way, (7) viral dsRNA induces (8) PKR-IRF3 signalling. The produced IFNs exert their activities in keratinocytes by (9) interacting with specific IFN-type receptor and (10) triggering JAK/STAT signalling pathways. IFN-α, IFN-β and IFN-λ interact with receptors associated with JAK1 and Tyk2 tyrosine kinases which induce the activation and dimer formation of the transcriptional factor STAT1/STAT2 by phosphorylation. This dimer forms a complex with IFN-stimulatory gene factor- 3γ (ISGF-3γ), also called IFN regulatory factor-9 (IRF-9) or P48, which bind to the ISRE sequence of DNA. In turn, IFN-γ binds to receptors associated with Jak1 and Jak2 tyrosine kinases that induce the formation of the Stat1/Stat1 homodimer. Finally, (11) the binding of transcription factors to specific responsive elements (i.e. ISRE and GAS) of DNA leads to (12) ISGs expression [99]. This IFN-induced activities create an antiviral state which leads to the destruction of infected cells with episomal HPV [90], whereas cells with integrated viral DNA can survive and transcription of E6-E7 oncogenes are no longer regulated by E2 leading to persistent infection and cancer formation [90]

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