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

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 activati on in response to IFN-alpha but not IFN-gamma. This inhibitory effect is no t shared by the 'benign' HPV-11 E6, The DNA-binding and transactivation cap acities of the transcription factor ISGF3 are diminished in cells expressin g HPV-18 E6 after IFN-alpha treatment as a result of decreased tyrosine pho sphorylation of Tyk2, STAT2 and STAT1. However, HPV-18 E6 does not affect t he induction of tyrosine phosphorylation and DNA-binding of STAT1 by IFN-ga mma. In addition, HPV E6 proteins physically interact,vith Tyk2, This inter action takes place preferably with HPV-18 E6 and to a lesser extent with HP V-11 E6. The E6/Tyk2 interaction requires the JH(6)-JH(7) domains of Tyk2, which are important for Tyk2 binding to the cytoplasmic portion of IFN-alph a 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, a t least in part, by the ability of E6 to interact with and impair Tyk2 acti vation.