The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

2.50
Hdl Handle:
http://hdl.handle.net/10033/620935
Title:
The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.
Authors:
Chan, Baca; Gonçalves Magalhães, Vladimir; Lemmermann, Niels A W; Juranić Lisnić, Vanda; Stempel, Markus; Bussey, Kendra A; Reimer, Elisa; Podlech, Jürgen; Lienenklaus, Stefan; Reddehase, Matthias J; Jonjić, Stipan; Brinkmann, Melanie M
Abstract:
The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.
Citation:
The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. 2017, 13 (5):e1006382 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
May-2017
URI:
http://hdl.handle.net/10033/620935
DOI:
10.1371/journal.ppat.1006382
PubMed ID:
28542326
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
junior research group immunomodulation (VIMM)

Full metadata record

DC FieldValue Language
dc.contributor.authorChan, Bacaen
dc.contributor.authorGonçalves Magalhães, Vladimiren
dc.contributor.authorLemmermann, Niels A Wen
dc.contributor.authorJuranić Lisnić, Vandaen
dc.contributor.authorStempel, Markusen
dc.contributor.authorBussey, Kendra Aen
dc.contributor.authorReimer, Elisaen
dc.contributor.authorPodlech, Jürgenen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorReddehase, Matthias Jen
dc.contributor.authorJonjić, Stipanen
dc.contributor.authorBrinkmann, Melanie Men
dc.date.accessioned2017-06-08T14:38:25Z-
dc.date.available2017-06-08T14:38:25Z-
dc.date.issued2017-05-
dc.identifier.citationThe murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. 2017, 13 (5):e1006382 PLoS Pathog.en
dc.identifier.issn1553-7374-
dc.identifier.pmid28542326-
dc.identifier.doi10.1371/journal.ppat.1006382-
dc.identifier.urihttp://hdl.handle.net/10033/620935-
dc.description.abstractThe type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleThe murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7., 38124 Braunschweig, Germany.en
dc.identifier.journalPLoS pathogensen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.