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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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DNA-Binding Proteins / physiology
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Enzyme Activation
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Humans
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Interferon-Stimulated Gene Factor 3
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interferon-alpha / genetics
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Interferon-alpha / physiology*
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Interferon-gamma / genetics
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Interferon-gamma / physiology
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Janus Kinase 2
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Multienzyme Complexes / physiology
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Oncogene Proteins, Viral / physiology*
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Papillomaviridae / physiology*
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Phosphorylation
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / isolation & purification
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology*
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Proteins / chemistry
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Proteins / isolation & purification
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Proteins / metabolism*
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Proteins / physiology
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Proto-Oncogene Proteins*
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STAT1 Transcription Factor
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STAT2 Transcription Factor
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Signal Transduction / physiology
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TYK2 Kinase
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Trans-Activators / physiology*
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Transcription Factors / physiology
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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E6 protein, Human papillomavirus type 18
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IRF9 protein, human
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Interferon-Stimulated Gene Factor 3
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interferon-alpha
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Multienzyme Complexes
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Oncogene Proteins, Viral
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Proteins
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Proto-Oncogene Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT2 Transcription Factor
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STAT2 protein, human
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Trans-Activators
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Transcription Factors
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Interferon-gamma
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2
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TYK2 Kinase
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TYK2 protein, human