title: Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte's innate immune response.
abstract: Persistent infection of basal keratinocytes with high-risk human papillomavirus (hrHPV) may cause cancer. Keratinocytes are equipped with different pattern recognition receptors (PRRs) but hrHPV has developed ways to dampen their signals resulting in minimal inflammation and evasion of host immunity for sustained periods of time. To understand the mechanisms underlying hrHPV's capacity to evade immunity, we studied PRR signaling in non, newly, and persistently hrHPV-infected keratinocytes. We found that active infection with hrHPV hampered the relay of signals downstream of the PRRs to the nucleus, thereby affecting the production of type-I interferon and pro-inflammatory cytokines and chemokines. This suppression was shown to depend on hrHPV-induced expression of the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in keratinocytes. UCHL1 accomplished this by inhibiting tumor necrosis factor receptor-associated factor 3 (TRAF3) K63 poly-ubiquitination which lead to lower levels of TRAF3 bound to TANK-binding kinase 1 and a reduced phosphorylation of interferon regulatory factor 3. Furthermore, UCHL1 mediated the degradation of the NF-kappa-B essential modulator with as result the suppression of p65 phosphorylation and canonical NF-κB signaling. We conclude that hrHPV exploits the cellular protein UCHL1 to evade host innate immunity by suppressing PRR-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response. This identifies UCHL1 as a negative regulator of PRR-induced immune responses and consequently its virus-increased expression as a strategy for hrHPV to persist.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rezaul
authors.initials: R
authors.lastname: Karim
authors.forename: Bart
authors.initials: B
authors.lastname: Tummers
authors.forename: Craig
authors.initials: C
authors.lastname: Meyers
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Biryukov
authors.forename: Samina
authors.initials: S
authors.lastname: Alam
authors.forename: Claude
authors.initials: C
authors.lastname: Backendorf
authors.forename: Veena
authors.initials: V
authors.lastname: Jha
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Daniele
authors.initials: D
authors.lastname: Guardavaccaro
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D052162:Human papillomavirus 16 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D015603:Keratinocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D030361:Papillomavirus Infections / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis / Q000276:immunology*; D054875:Ubiquitination / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D016207:Cytokines; C498143:RELA protein, human; D048008:TNF Receptor-Associated Factor 3; D051996:Transcription Factor RelA; C482860:UCHL1 protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D043222:Ubiquitin Thiolesterase