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.
Highlights
Human papillomaviruses (HPVs) are absolutely species-specific small double-stranded DNA viruses
We conclude that high-risk human papillomavirus (hrHPV) exploits the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) to evade host innate immunity by suppressing pattern recognition receptors (PRRs)-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response
Whereas keratinocytes – the cells infected by hrHPV – are equipped with different receptors allowing them to recognize invading pathogens and to activate the immune system, hrHPV has developed ways to evade the host’s immune response for sustained periods of time
Summary
Human papillomaviruses (HPVs) are absolutely species-specific small double-stranded DNA viruses. Viruses and microbes contain pathogen-associated molecular patterns that are recognized by the host’s pattern recognition receptors (PRRs), comprising the Toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) [5]. While all of these receptors activate signaling cascades that lead to activation of NF-kB via the canonical route, only RLRs and some TLRs activate interferon regulatory factors (IRFs) which induce the production of type I interferons (IFN) and other effector molecules [6]. Poly-ubiquitination of TRAF and NEMO allows downstream signaling whereas disassembly of the formed poly-ubiquitin chains by deubiquitinating enzymes provides a mechanism for downregulating immune responses [6,7]
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