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

Abstract

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.

Inhibition of kinase IKKβ suppresses cellular abnormalities induced by the human papillomavirus oncoprotein HPV 18E6

“…In this study we identify IKKβ as a mediator of the HPV 18 E6 and hUBE3A-induced cellular defects in both fly and human cancer models. This is consistent with previous studies demonstrating that HPV 16 E6 interacts with components of the innate immune pathway, including IKKβ, and it activates the NF-κB transcription factor 52,53 . The role of the innate immune system in HPV infection and cancer progression is not well understood.…”

Unusual prevalence of high-risk genotypes of human papillomavirus in a group of women with neoplastic lesions and cervical cancer from Central Mexico

“…This diversity could be related to the phylogenetic associations between different HPV species or with the interaction of different oncoproteins (E6, E7) with proteins involved in apoptosis (it has been reported that different genotypes differentially increase myc expression [51] [52]) or E6, which can suppress the transcription of TLR9 [53] or genes involved in interferon signaling (STAT), producing an inactivation state of the immune system and the inflammatory response associated to the presence of the viral infection [54].…”

Immune Response of Plasmacytoid Dendritic Cells Stimulated by Human Papillomavirus (HPV) E6 in an In Vitro System

“…The HPV16 E6 prepared in this study might have promoted NF-kB activation by upregulating MyD88 and TRAF6, whereas Caski cells might have inhibited NF-kB signaling via the E7 protein. Hence, the activation of NF-kB pathway and the expression of MyD88 and TRAF6 proteins were affected by HPV-positive cells at different infection stages [12].…”