Analysis of Multiple HPV E6 PDZ Interactions Defines Type-Specific PDZ Fingerprints That Predict Oncogenic Potential

Area of Science:

• Virology and Molecular Biology
• Oncogenesis
• Protein-Protein Interactions

Background:

• High-risk Human Papillomavirus (HPV) E6 oncoproteins possess a PDZ-binding motif (PBM) crucial for their function.
• The presence of PBMs in both cancer-causing and non-cancer-causing HPV E6 proteins necessitates investigation into their functional distinctions.

Purpose of the Study:

• To investigate functional differences between various HPV E6 PBMs.
• To identify PDZ target fingerprints for E6 PBMs from different HPV types.
• To correlate PDZ target interactions with oncogenic potential.

Main Methods:

• Employed an unbiased proteomic approach in keratinocytes to compare E6 PBM interaction profiles.
• Analyzed E6 PBMs from 7 cancer-causing, 3 weakly associated, and 1 benign HPV type.

Main Results:

• Demonstrated a significant increase in PDZ target binding with escalating HPV oncogenic potential.
• HPV-16 and HPV-18 PBMs exhibited the highest PDZ target selection flexibility.
• Interaction with hScrib directly correlated with increased oncogenic potential, while hDlg binding was conserved across all analyzed HPV E6 PBMs.
• Identified ZO-2 and β-2 syntrophin as novel PDZ domain targets for a subset of high-risk HPV types.

Conclusions:

• HPV E6 PBMs display varying PDZ target interaction profiles linked to oncogenic potential.
• The conserved interaction with hDlg suggests its role in early HPV evolution and niche adaptation.
• Novel targets ZO-2 and β-2 syntrophin highlight new mechanisms of HPV-mediated cellular disruption.