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The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by
S Li1, S Labrecque, M C Gauzzi
1Department of Oncology, McGill University, Montreal, Quebec, Canada.
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.
Insights
Human papillomavirus (HPV) type 18 E6 protein inhibits interferon-alpha signaling by blocking Jak-STAT activation. This interaction with Tyk2 kinase is specific to HPV-18 E6 and impairs the antiviral response.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Interferon (IFN) signaling is crucial for antiviral defense.
- Human papillomavirus (HPV) oncoproteins, particularly E6, are implicated in viral pathogenesis and immune evasion.
- The Jak-STAT pathway is a key mediator of IFN responses.
Purpose of the Study:
- To investigate the impact of HPV E6 proteins on IFN signaling pathways.
- To determine if HPV-18 E6 differentially affects IFN-alpha and IFN-gamma signaling.
- To elucidate the molecular mechanism by which HPV-18 E6 might interfere with IFN signaling.
Main Methods:
- Expression of HPV-18 E6 and HPV-11 E6 in human HT1080 cells.
- Stimulation with IFN-alpha and IFN-gamma.
- Analysis of Jak-STAT pathway activation, including tyrosine phosphorylation of Tyk2, STAT1, and STAT2.
- Assessment of ISGF3 DNA-binding and transactivation.
- Co-immunoprecipitation assays to detect physical interactions between HPV E6 proteins and Tyk2.
Main Results:
- HPV-18 E6 expression inhibited IFN-alpha-induced Jak-STAT activation, but not IFN-gamma-induced activation.
- This inhibition was associated with decreased tyrosine phosphorylation of Tyk2, STAT2, and STAT1.
- HPV-18 E6 reduced the DNA-binding and transactivation capacity of ISGF3.
- HPV-18 E6 and, to a lesser extent, HPV-11 E6 physically interacted with Tyk2 kinase.
- The interaction mapped to the JH6-JH7 domains of Tyk2, crucial for IFNAR1 binding.
Conclusions:
- HPV-18 E6 actively inhibits the IFN-alpha-induced Jak-STAT pathway.
- The mechanism involves direct interaction with and impairment of Tyk2 activation.
- This interaction may contribute to immune evasion strategies employed by HPV-18.
- HPV-11 E6 exhibits a weaker inhibitory effect, suggesting E6 protein variability in immune modulation.