Human papillomavirus (HPV) 16 E6 oncoprotein targets the Toll-like receptor pathway

Cervical cancer is one of the leading causes of death in women worldwide and is etiologically linked to human papillomavirus (HPV) infection. Viral early proteins E6 and E7 manipulate cellular functions to promote the virus life cycle and are essential to the cellular transformation process. The innate immune system plays a pivotal role in the natural history of HPV infection. Among the various proteins that mediate the innate immune response, Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and initiate the immune response. The objective of this study was to identify HPV E6 protein interaction partners in the TLR signalling pathway that may play a role in the immune response against HPV. Six TLR pathway proteins were shown to interact with HPV16 E6: myeloid differentiation primary response protein (MyD88), TIR domain-containing adapter molecule 1 (TRIF), interleukin-1 receptor-associated kinase-like (IRAK) 2, TNF receptor-associated factor (TRAF) 6, I-κB kinase beta (IKKβ) and I-κB kinase epsilon (IKKε). The interaction site of IKKε with E6 is located in the region containing the enzyme catalytic site, suggesting an influence of E6 on the activation of IKKε target proteins. HPV16 E6 potentiated the activation of NF-κB by various TLR pathway members. These results suggest that HPV16 has the ability to interfere with components of the immune response, contributing to HPV carcinogenesis.