The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter

Hasan, Uzma; Zannetti, Claudia; Parroche, Peggy; Goutagny, Nadège; Malfroy, Marine; Roblot, Guillaume; Carreira, Christine; Hussain, Ishraq; Müller, M.; Taylor‐Papadimitriou, Joyce; Picard, Didier; Sylla, Bakary S.; Trinchieri, Giorgio; Medzhitov, Ruslan; Tommasino, Massimo

doi:10.1084/jem.20122394

Cited by 153 publications

(144 citation statements)

References 84 publications

(130 reference statements)

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“…The expression of these oncoproteins inhibits the immune system response to hrHPV and aids in the persistency of the infection. The oncoproteins could downregulate TLR9 expression, a virus DNA sensor, which is necessary to activate antigen-presenting cells (17), but they could also reduce the expression of transporter-associated antigen processing 1, blocking the activation of specific T lymphocytes. It has been confirmed that neoplastic cervical keratinocytes (KCs) expressing high levels of E6 and E7 oncoproteins could escape the attack from cytotoxic T cells (CTLs) (18).…”

Section: Effect Of Human Papillomavirus Infection On the Immune Systementioning

confidence: 99%

Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer

et al. 2015

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Abstract. Human papillomavirus (HPV) is widely known as a cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. The mechanisms involved have been studied by numerous studies. The integration of the virus genome into the host cells results in the abnormal regulation of cell cycle control. HPV can also induce immune evasion of the infected cells, which enable the virus to be undetectable for long periods of time. The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The present review elaborates on the roles of several types of immune cells, such as macrophages and natural killer cells, which are classified as innate immune cells, and dendritic cells (DCs), cluster of differentiation (CD)4 + /CD8 + T cells and regulatory T cells, which are classified as adaptive immune cells. HPV infection could effect the differentiation of these immune cells in a unique way, resulting in the host's immune tolerance to the infection. The immune system modifications induced by HPV infection include tumor-associated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and downregulated DC activation and maturation. To date, numerous types of preventative vaccines have been created to slow down carcinogenesis. Immune response activation-based therapeutic vaccine is becoming more and more attractive for the treatment of HPV-associated diseases.

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Section: Effect Of Human Papillomavirus Infection On the Immune Systementioning

confidence: 99%

Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer

et al. 2015

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“…In addition to their ability to promote cellular transformation, human cancer-associated viruses deregulate pathways linked to the host immune response, thus favoring the persistence of the infection, which is an essential condition for cancer development (14)(15)(16). Mucosal high-risk HPV16, Epstein-Barr virus (EBV), Merkel cell polyomavirus, and hepatitis B virus alter the expression of Toll-like receptors (TLRs), which are fundamental players in the innate immune response, acting as pattern recognition receptors (PRRs) (17,18).…”

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confidence: 99%

“…Mucosal high-risk HPV16, Epstein-Barr virus (EBV), Merkel cell polyomavirus, and hepatitis B virus alter the expression of Toll-like receptors (TLRs), which are fundamental players in the innate immune response, acting as pattern recognition receptors (PRRs) (17,18). In particular, all four of these oncogenic viruses, using distinct mechanisms, downregulate the transcription of TLR9, which resides in the endosomal compartments of the cell and senses viral double-stranded DNA (16,(19)(20)(21)(22)(23)(24). To gain further insights into the possible role of HPV38 in human carcinogenesis, in this study, we investigated whether HPV38 E6 and E7 have the ability to deregulate TLR9 expression.…”

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confidence: 99%

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

Pacini

Savini

Ghittoni

et al. 2015

J Virol

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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 ⌬Np73␣, an antagonist of p53 and p73. Inhibition of ⌬Np73␣ expression by antisense oligonucleotide in HPV38 E6/E7 HFK strongly rescues mRNA levels of TLR9, highlighting a key role of ⌬Np73␣ in this event. Chromatin immunoprecipitation experiments showed that ⌬Np73␣ is part of a negative transcriptional regulatory complex with IB kinase beta (IKK␤) that binds to a NF-B 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 HPV38 E6/E7 cells resulted in an accumulation of the cell cycle inhibitors p21 WAF1 and p27 Kip1 , decreased CDK2-associated kinase activity, and inhibition of cellular proliferation. In summary, our data show that HPV38, similarly to other viruses with well-known oncogenic activity, can downregulate TLR9 expression. In addition, they highlight a new role for TLR9 in cell cycle regulation. IMPORTANCEThe mucosal high-risk HPV types have been clearly associated with human carcinogenesis. Emerging lines of evidence suggest the involvement of certain cutaneous HPV types in development of skin squamous cell carcinoma, although this association is still under debate. Oncogenic viruses have evolved different strategies to hijack the host immune system in order to guarantee the persistence of the infection. Their capability to evade the immune system is as important as their ability to promote cellular transformation. Therefore, understanding the viral mechanisms involved in viral persistence is a valid tool to evaluate their potential role in human carcinogenesis. Here, we show that E6 and E7 oncoproteins from the cutaneous HPV38 downregulate the expression of the double-stranded DNA sensor TLR9 of innate immunity. We also present evidence that the HPV38-mediated downregulation of TLR9 expression, in addition to its potential impact on the innate immune response, is linked to cell cycle deregulation. In addition to the well-characterized mucosal high-risk human papillomaviruses (HPV), a subgroup of cutaneous HPV types belonging to the genus beta of the HPV phylogenetic tree appears to be associated with human carcinogenesis (1-3). These HPV types are suspected to be involved together with UV radiation in the development of nonmelanoma skin cancer (4, 5). Beta HPV types were originally isolat...

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“…In addition to their ability to promote cellular transformation, oncogenic viruses have developed mechanisms to target cellular pathways related to innate and adaptive immune surveillance (12)(13)(14)(15)(16)(17). It is believed that these properties facilitate the establishment of a persistent/chronic infection, a key step in virus-mediated carcinogenesis.…”

mentioning

confidence: 99%

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

Sattar

Shuda

Gheit

et al. 2013

J Virol

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The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter

Abstract: HPV16-positive cervical cancer lesions contain NFκB–ERα nuclear complexes to repress the TLR9 promoter.

Cited by 153 publications

References 84 publications

Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer

Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer

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

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

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