title: The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter.
abstract: Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50-p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.
authors.affiliation: Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon 69008, France. uzma.hasan@inserm.fr
authors.forename: Uzma A
authors.initials: UA
authors.lastname: Hasan
authors.forename: Claudia
authors.initials: C
authors.lastname: Zannetti
authors.forename: Peggy
authors.initials: P
authors.lastname: Parroche
authors.forename: Nadège
authors.initials: N
authors.lastname: Goutagny
authors.forename: Marine
authors.initials: M
authors.lastname: Malfroy
authors.forename: Guillaume
authors.initials: G
authors.lastname: Roblot
authors.forename: Christine
authors.initials: C
authors.lastname: Carreira
authors.forename: Ishraq
authors.initials: I
authors.lastname: Hussain
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
authors.forename: Joyce
authors.initials: J
authors.lastname: Taylor-Papadimitriou
authors.forename: Didier
authors.initials: D
authors.lastname: Picard
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D052162:Human papillomavirus 16 / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D050725:Papillomavirus E7 Proteins / Q000276:immunology*; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics*
chemical_list: D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C059731:oncogene protein E7, Human papillomavirus type 16