Abstract
Human papillomavirus (HPV) is the most prevalent sexually transmitted infection, affecting an estimated 11% of the world’s population. The high-risk HPV types (HR HPV) account for approximately 5% of the global burden of cancer and thus cause high morbidity and mortality. Although it is known that persistent infection with HR HPV is the greatest risk factor for developing HPV-associated cancer, and that the HPV early proteins E6 and E7 dysregulate immune detection by its host cells, the mechanisms of immune evasion by HR HPV are not well understood. Previous work in the laboratory identified the endogenous cytoplasmic host protein NFX1-123 as a binding partner of the HR HPV type 16 oncoprotein E6 (16E6). Together NFX1-123 and 16E6 affect cellular growth, differentiation, and immortalization genes and pathways. In a whole genome microarray, human foreskin keratinocytes (HFKs) stably expressing 16E6 and overexpressing NFX1-123 showed a diverse set of innate immune genes downregulated two-fold or more when compared to 16E6 cells with endogenous NFX1-123. We demonstrated that 16E6 and NFX1-123 decreased expression of pro-inflammatory cytokines and interferon-stimulated genes (ISGs) in 16E6 HFKs at the mRNA and protein level. Knock down of NFX1-123 in 16E6 HFKs resulted in a derepression of innate immune genes, pointing to the requirement of NFX1-123 for immune regulation in the context of 16E6. Studies using immunofluorescent microscopy revealed that 16E6 and NFX1-123 disturbed the normal localization of signaling proteins involved in initiating the immune response. This study identifies NFX1-123 as a critical host protein partner through which 16E6 is able to subvert the immune response and in turn permit a long-lived HR HPV infection.
Highlights
There are over 200 types of human papillomaviruses (HPV), which infect keratinocytes of the stratified squamous epithelium [1]
Quantitative real-time PCR analysis showed that for each independent 16 oncoprotein E6 (16E6) human foreskin keratinocytes (HFKs) cell line, there was nearly a two-fold increase in NFX1123 mRNA expression in FLAG-tagged NFX1-123 construct (FN123) cells versus control (Fig 1B) that was reflected at the protein level (Fig 1C)
The work presented in this study establishes a novel role in immune evasion for the protein partners HPV type 16 E6 and NFX1-123
Summary
There are over 200 types of human papillomaviruses (HPV), which infect keratinocytes of the stratified squamous epithelium [1]. Those that target mucosal epithelium are further categorized as low-risk HPV (LR HPV) or high-risk HPV (HR HPV) based on their epidemiologic association with cancer [2,3]. The immune response clears most of these infections, a persistent infection remains for some people [9,10,11,12]. The factors that contribute to a persistent HR HPV infection are not fully defined, but it is clear that effective avoidance of the host immune detection and response is integral to this process
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.