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

PLoS Pathogens

Rezaul Karim¹  Daniele Guardavaccaro¹  Gert-Jan B. van Ommen²  Jennifer L. Biryukov²  Craig Meyers²  Cornelis J. M. Melief³  Bart Tummers³  Judith M. Boer³  Veena Jha⁴  Claude Backendorf⁴  Samina Alam⁴  Sjoerd H. van der Burg⁵  Rienk Offringa⁶ 

[1] Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands;Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands;Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America;Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands;Laboratory of Molecular Genetics, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands

关键词: Keratinocytes;    Cytokines;    Gene expression;    Immunoprecipitation;    Immune receptor signaling;    HPV-16;    Small interfering RNAs;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1003384

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY