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

Oncogene. 1999 Oct 14;18(42):5727-37. doi: 10.1038/sj.onc.1202960.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / physiology
  • Enzyme Activation
  • Humans
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha / genetics
  • Interferon-alpha / physiology*
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology
  • Janus Kinase 2
  • Multienzyme Complexes / physiology
  • Oncogene Proteins, Viral / physiology*
  • Papillomaviridae / physiology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / isolation & purification
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology*
  • Proteins / chemistry
  • Proteins / isolation & purification
  • Proteins / metabolism*
  • Proteins / physiology
  • Proto-Oncogene Proteins*
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Signal Transduction / physiology
  • TYK2 Kinase
  • Trans-Activators / physiology*
  • Transcription Factors / physiology
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 18
  • IRF9 protein, human
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Multienzyme Complexes
  • Oncogene Proteins, Viral
  • Proteins
  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Trans-Activators
  • Transcription Factors
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Janus Kinase 2
  • TYK2 Kinase
  • TYK2 protein, human