title: The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha.
abstract: We have examined the effects of human papilloma virus (HPV) E6 proteins on interferon (IFN) signaling. Here we show that expression of the 'malignant' HPV-18 E6 in human HT1080 cells results in inhibition of Jak-STAT activation in response to IFN-alpha but not IFN-gamma. This inhibitory effect is not shared by the 'benign' HPV-11 E6. The DNA-binding and transactivation capacities of the transcription factor ISGF3 are diminished in cells expressing HPV-18 E6 after IFN-alpha treatment as a result of decreased tyrosine phosphorylation of Tyk2, STAT2 and STAT1. However, HPV-18 E6 does not affect the induction of tyrosine phosphorylation and DNA-binding of STAT1 by IFN-gamma. In addition, HPV E6 proteins physically interact with Tyk2. This interaction takes place preferably with HPV-18 E6 and to a lesser extent with HPV-11 E6. The E6/Tyk2 interaction requires the JH6-JH7 domains of Tyk2, which are important for Tyk2 binding to the cytoplasmic portion of IFN-alpha receptor 1 (IFNAR1). These findings demonstrate an inhibitory role of HPV-18 E6 in the IFN-alpha-induced Jak-STAT pathway, which may be explained, at least in part, by the ability of E6 to interact with and impair Tyk2 activation.
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Labrecque
authors.forename: M C
authors.initials: MC
authors.lastname: Gauzzi
authors.forename: A R
authors.initials: AR
authors.lastname: Cuddihy
authors.forename: A H
authors.initials: AH
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Pellegrini
authors.forename: G J
authors.initials: GJ
authors.lastname: Matlashewski
authors.forename: A E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D053614:Janus Kinase 2; D009097:Multienzyme Complexes / Q000502:physiology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D027383:Papillomaviridae / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human