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Viruses. 2018 Oct 16;10(10). pii: E567. doi: 10.3390/v10100567.

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

Author information

1
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. matteo.biolatti@unito.it.
2
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. valentina.delloste@unito.it.
3
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. sara.scutera@unito.it.
4
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. francesca.gugliesi@unito.it.
5
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. gloria.griffante@unito.it.
6
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. marco.deandrea@unito.it.
7
Intrinsic Immunity Unit, CAAD⁻Center for Translational Research on Autoimmune and Allergic Disease, University of Piemonte Orientale, 28100 Novara, Italy. marco.deandrea@unito.it.
8
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. tiziana.musso@unito.it.
9
Department of Public Health and Pediatric Sciences, University of Turin, 10126 Turin, Italy. santo.landolfo@unito.it.

Abstract

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.

KEYWORDS:

caspase-8; human cytomegalovirus (HCMV); inflammasome; interleukin-1β (IL-1β); pp65

PMID:
30332797
PMCID:
PMC6213739
DOI:
10.3390/v10100567
[Indexed for MEDLINE]
Free PMC Article

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