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The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α

Oncogene volume 18, pages 5727–5737 (1999)Cite this article

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-α but not IFN-γ. 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-α 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-γ. 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-α receptor 1 (IFNAR1). These findings demonstrate an inhibitory role of HPV-18 E6 in the IFN-α-induced Jak-STAT pathway, which may be explained, at least in part, by the ability of E6 to interact with and impair Tyk2 activation.

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Acknowledgements

We thank L Banks for GST-fusion proteins of HPV-16 E6 and helpful suggestions; O Colamonici for the GST-IFNAR1 fusion protein and antibodies to IFNAR1; R Pine for 15KWTtkGL3 construct; G Stark for 2fTGH and U1A cells; T Decker for ISG-15 and IFP-53 cDNAs and useful suggestions. This work has been primarily supported by a grant from The Cancer Research Society (CRS) Inc. to AE Koromilas, and by grants from the Medical Research Council (MRC) of Canada and The National Cancer Institute of Canada (NCIC) to AE Koromilas and G Matlashewski. Work at the Institute Pasteur was in part supported by a grant to S Pelligrini by the Association pour la Recherche contre le Cancer. AR Cuddihy is supported by a CRS studentship and AHT Wong by a NCIC scholarship and MC Gauzzi by a fellowship from the Fondation pour la Recherche Medicale. AE Koromilas is a member of the Terry Fox Group of Molecular Oncology and a recipient of an MRC Scientist Award.

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Authors and Affiliations

  1. Department of Oncology, McGill University, Montreal, Quebec, Canada

    Suiyang Li, Andrew R Cuddihy, Andrew HT Wong & Antonis E Koromilas

  2. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Antonis E Koromilas

  3. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    Antonis E Koromilas

  4. Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada

    Antonis E Koromilas

  5. Institute of Parasitology, McGill University, Montreal, Quebec, Canada

    Sylvie Labrecque & Gregory J Matlashewski

  6. McGill Cancer Center, McGill University, Montreal, Quebec, Canada

    Sylvie Labrecque & Gregory J Matlashewski

  7. Pasteur Institute, INSERM U 276, 75724, Paris, Cedex 15, France

    M Cristina Gauzzi & Sandra Pellegrini

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  1. Suiyang Li
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Li, S., Labrecque, S., Gauzzi, M. et al. The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α. Oncogene 18, 5727–5737 (1999). https://doi.org/10.1038/sj.onc.1202960

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