title: The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation.
abstract: High-risk human papillomaviruses (hrHPVs) infect keratinocytes and successfully evade host immunity despite the fact that keratinocytes are well equipped to respond to innate and adaptive immune signals. Using non-infected and freshly established or persistent hrHPV-infected keratinocytes we show that hrHPV impairs the acetylation of NFκB/RelA K310 in keratinocytes. As a consequence, keratinocytes display a decreased pro-inflammatory cytokine production and immune cell attraction in response to stimuli of the innate or adaptive immune pathways. HPV accomplishes this by augmenting the expression of interferon-related developmental regulator 1 (IFRD1) in an EGFR-dependent manner. Restoration of NFκB/RelA acetylation by IFRD1 shRNA, cetuximab treatment or the HDAC1/3 inhibitor entinostat increases basal and induced cytokine expression. Similar observations are made in IFRD1-overexpressing HPV-induced cancer cells. Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Tummers
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Goedemans
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Laetitia P L
authors.initials: LP
authors.lastname: Pelascini
authors.affiliation: Center for Gynaecological Oncology, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Gynaecology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Edith M G
authors.initials: EM
authors.lastname: van Esch
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Meyers
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D057131:Immune Evasion; D007371:Interferon-gamma / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D016207:Cytokines; C490045:IFRD1 protein, human; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D066246:ErbB Receptors; D006655:Histone Deacetylases