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The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity

Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1β into its mature secreted form, the mechanism by...

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Autores principales: Biolatti, Matteo, Dell’Oste, Valentina, Scutera, Sara, Gugliesi, Francesca, Griffante, Gloria, De Andrea, Marco, Musso, Tiziana, Landolfo, Santo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213739/
https://www.ncbi.nlm.nih.gov/pubmed/30332797
http://dx.doi.org/10.3390/v10100567
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author Biolatti, Matteo
Dell’Oste, Valentina
Scutera, Sara
Gugliesi, Francesca
Griffante, Gloria
De Andrea, Marco
Musso, Tiziana
Landolfo, Santo
author_facet Biolatti, Matteo
Dell’Oste, Valentina
Scutera, Sara
Gugliesi, Francesca
Griffante, Gloria
De Andrea, Marco
Musso, Tiziana
Landolfo, Santo
author_sort Biolatti, Matteo
collection PubMed
description Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1β into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1β production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1β compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1β. Furthermore, we show that enhanced IL-1β production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-κB. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1β activation pathway where caspase-8 promotes IL-1β maturation independently of caspase-1. Altogether, our findings provide novel mechanistic insights into the interplay between HCMV and the inflammasome system and raise the possibility of targeting pp65 to treat HCMV infection.
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spelling pubmed-62137392018-11-09 The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity Biolatti, Matteo Dell’Oste, Valentina Scutera, Sara Gugliesi, Francesca Griffante, Gloria De Andrea, Marco Musso, Tiziana Landolfo, Santo Viruses Communication Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1β into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1β production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1β compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1β. Furthermore, we show that enhanced IL-1β production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-κB. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1β activation pathway where caspase-8 promotes IL-1β maturation independently of caspase-1. Altogether, our findings provide novel mechanistic insights into the interplay between HCMV and the inflammasome system and raise the possibility of targeting pp65 to treat HCMV infection. MDPI 2018-10-16 /pmc/articles/PMC6213739/ /pubmed/30332797 http://dx.doi.org/10.3390/v10100567 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Biolatti, Matteo
Dell’Oste, Valentina
Scutera, Sara
Gugliesi, Francesca
Griffante, Gloria
De Andrea, Marco
Musso, Tiziana
Landolfo, Santo
The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title_full The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title_fullStr The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title_full_unstemmed The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title_short The Viral Tegument Protein pp65 Impairs Transcriptional Upregulation of IL-1β by Human Cytomegalovirus through Inhibition of NF-kB Activity
title_sort viral tegument protein pp65 impairs transcriptional upregulation of il-1β by human cytomegalovirus through inhibition of nf-kb activity
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213739/
https://www.ncbi.nlm.nih.gov/pubmed/30332797
http://dx.doi.org/10.3390/v10100567
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