Research Article: Human Papillomavirus (HPV) Upregulates the Cellular Deubiquitinase UCHL1 to Suppress the Keratinocyte’s Innate Immune Response

Date Published: May 23, 2013

Publisher: Public Library of Science

Author(s): 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, John Hiscott.


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.

Partial Text

Human papillomaviruses (HPVs) are absolutely species-specific small double-stranded DNA viruses. Persistent infections with a number of HPVs, predominantly types 16 and 18, can induce cancers of the anogenitalia as well as of the head and neck region. These so-called high-risk HPVs (hrHPVs) are widespread within all human populations where they are commonly transmitted by sexual contact [1]. The undifferentiated keratinocytes of the squamous epithelia are the primary target for hrHPV [2] where it establishes an infection that can last for up to 2 years, indicating that hrHPV has evolved mechanisms to effectively evade the innate and adaptive immune mechanisms protecting the majority of immunocompetent hosts [3], [4].

We have employed a unique model for hrHPV infection to examine the potential mechanisms underlying the capacity of hrHPV to evade host immunity by suppression of the innate immune response [10]. We utilized primary KC cultures that were newly infected with HPV16 virions or primary KCs stably maintaining the episomal hrHPV genome to show that despite the expression of multiple PRRs the production of IFNβ and pro-inflammatory cytokines and chemokines is suppressed by hrHPV as a consequence of reduced PRR signaling. We provided firm evidence that this suppression depends on the hrHPV-induced upregulation of the cellular ubiquitin-modifying enzyme UCHL1 in infected primary KCs.




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