Downregulation of Toll-Like Receptor 9 Expression by Beta Human Papillomavirus 38 and Implications for Cell Cycle Control

Journal of Virology
Laura PaciniMassimo Tommasino

Abstract

Innate immunity is the first line of host defense against infections. Many oncogenic viruses can deregulate several immune-related pathways to guarantee the persistence of the infection. Here, we show that the cutaneous human papillomavirus 38 (HPV38) E6 and E7 oncoproteins suppress the expression of the double-stranded DNA sensor Toll-like receptor 9 (TLR9) in human foreskin keratinocytes (HFK), a key mediator of the antiviral innate immune host response. In particular, HPV38 E7 induces TLR9 mRNA downregulation by promoting accumulation of ΔNp73α, an antagonist of p53 and p73. Inhibition of ΔNp73α expression by antisense oligonucleotide in HPV38 E6/E7 HFK strongly rescues mRNA levels of TLR9, highlighting a key role of ΔNp73α in this event. Chromatin immunoprecipitation experiments showed that ΔNp73α is part of a negative transcriptional regulatory complex with IκB kinase beta (IKKβ) that binds to a NF-κB responsive element within the TLR9 promoter. In addition, the Polycomb protein enhancer of zeste homolog 2 (EZH2), responsible for gene expression silencing, is also recruited into the complex, leading to histone 3 trimethylation at lysine 27 (H3K27me3) in the same region of the TLR9 promoter. Ectopic expression of TLR9 in HP...Continue Reading

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Citations

Nov 9, 2016·Virus Research·Shiyuan Hong, Laimonis A Laimins
Apr 8, 2017·Virus Research·Carlos SantosRui M Gil da Costa
Sep 3, 2017·International Journal of Cancer. Journal International Du Cancer·Alina Steinbach, Angelika B Riemer
Aug 19, 2017·Journal of Cancer Research and Clinical Oncology·Cecilia Martínez-CamposVicente Madrid-Marina
Feb 24, 2018·Scientific Reports·Mirian Galliote MoraleEnrique Boccardo
Apr 9, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Assunta VenutiSigrun Smola
Feb 18, 2017·The British Journal of Dermatology·A C Green, C M Olsen
Aug 21, 2019·Frontiers in Oncology·Chenhao ZhouIan Hector Frazer
Feb 6, 2017·Viral Immunology·Cecilia Martínez-CamposVicente Madrid-Marina
Aug 28, 2020·International Reviews of Immunology·Babban JeeShivendra Kumar Shahi
Aug 8, 2020·Scandinavian Journal of Immunology·Sonal YadavManisha Yadav
Mar 16, 2021·Tumour Virus Research·Arushi VatsLawrence Banks

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