Human Papillomavirus (HPV) Upregulates the Cellular Deubiquitinase UCHL1 to Suppress the Keratinocyte's Innate Immune Response

Rezaul Karim, Bart Tummers, Craig Meyers, Jennifer L. Biryukov, Samina Alam, Claude Backendorf, Veena Jha, Rienk Offringa, Gert Jan B. van Ommen, Cornelis J.M. Melief, Daniele Guardavaccaro, Judith M. Boer, Sjoerd H. van der Burg

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94 Scopus citations

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.

Original languageEnglish (US)
Article numbere1003384
JournalPLoS pathogens
Volume9
Issue number5
DOIs
StatePublished - May 2013

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Karim, R., Tummers, B., Meyers, C., Biryukov, J. L., Alam, S., Backendorf, C., Jha, V., Offringa, R., van Ommen, G. J. B., Melief, C. J. M., Guardavaccaro, D., Boer, J. M., & van der Burg, S. H. (2013). Human Papillomavirus (HPV) Upregulates the Cellular Deubiquitinase UCHL1 to Suppress the Keratinocyte's Innate Immune Response. PLoS pathogens, 9(5), [e1003384]. https://doi.org/10.1371/journal.ppat.1003384