Human Papillomavirus E6 interaction with cellular PDZ domain proteins modulates YAP nuclear localization.

HPV E6 oncoproteins associate with cellular PDZ proteins. In addition to previously identified cellular PDZ proteins, we found association of the HPV16 E6 PBM with the Dystrophin Glycoprotein Complex, LRCC1, and SLC9A3R2. HPV18 E6 had additional associations when lysates from adenomatous cell lines were used including LRPPRC, RLGAPB, EIF3A, SMC2 and 3, AMOT, AMOTL1, and ARHGEF1; some of these cellular PDZ proteins are implicated in the regulation of the YAP1 transcriptional co-activator. In keratinocytes, nuclear translocation of YAP1 was promoted by the complete HPV-16 genome, or by expression of the individual E6 or E7 oncoproteins; the activity of E6 required an intact PBM at the carboxy-terminus. This work demonstrates that E6 association with cellular PDZ proteins promotes the nuclear localization of YAP1. The ability of E6 to promote the nuclear transport of YAP1 thus identifies an E6 activity that could contribute to the transformation of cells by E6.