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Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1

Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms of BPLF1 exerted pot...

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Autores principales: Lui, Wai-Yin, Bharti, Aradhana, Wong, Nok-Hei Mickey, Jangra, Sonia, Botelho, Michael G., Yuen, Kit-San, Jin, Dong-Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9983872/
https://www.ncbi.nlm.nih.gov/pubmed/36802409
http://dx.doi.org/10.1371/journal.ppat.1011186
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author Lui, Wai-Yin
Bharti, Aradhana
Wong, Nok-Hei Mickey
Jangra, Sonia
Botelho, Michael G.
Yuen, Kit-San
Jin, Dong-Yan
author_facet Lui, Wai-Yin
Bharti, Aradhana
Wong, Nok-Hei Mickey
Jangra, Sonia
Botelho, Michael G.
Yuen, Kit-San
Jin, Dong-Yan
author_sort Lui, Wai-Yin
collection PubMed
description Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms of BPLF1 exerted potent suppressive effect on cGAS-STING-, RIG-I- and TBK1-induced IFN production. The observed suppression was reversed when DUB domain of BPLF1 was rendered catalytically inactive. The DUB activity of BPLF1 also facilitated EBV infection by counteracting cGAS-STING- and TBK1-mediated antiviral defense. BPLF1 associated with STING to act as an effective DUB targeting its K63-, K48- and K27-linked ubiquitin moieties. BPLF1 also catalyzed removal of K63- and K48-linked ubiquitin chains on TBK1 kinase. The DUB activity of BPLF1 was required for its suppression of TBK1-induced IRF3 dimerization. Importantly, in cells stably carrying EBV genome that encodes a catalytically inactive BPLF1, the virus failed to suppress type I IFN production upon activation of cGAS and STING. This study demonstrated IFN antagonism of BPLF1 mediated through DUB-dependent deubiquitination of STING and TBK1 leading to suppression of cGAS-STING and RIG-I-MAVS signaling.
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spelling pubmed-99838722023-03-04 Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1 Lui, Wai-Yin Bharti, Aradhana Wong, Nok-Hei Mickey Jangra, Sonia Botelho, Michael G. Yuen, Kit-San Jin, Dong-Yan PLoS Pathog Research Article Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms of BPLF1 exerted potent suppressive effect on cGAS-STING-, RIG-I- and TBK1-induced IFN production. The observed suppression was reversed when DUB domain of BPLF1 was rendered catalytically inactive. The DUB activity of BPLF1 also facilitated EBV infection by counteracting cGAS-STING- and TBK1-mediated antiviral defense. BPLF1 associated with STING to act as an effective DUB targeting its K63-, K48- and K27-linked ubiquitin moieties. BPLF1 also catalyzed removal of K63- and K48-linked ubiquitin chains on TBK1 kinase. The DUB activity of BPLF1 was required for its suppression of TBK1-induced IRF3 dimerization. Importantly, in cells stably carrying EBV genome that encodes a catalytically inactive BPLF1, the virus failed to suppress type I IFN production upon activation of cGAS and STING. This study demonstrated IFN antagonism of BPLF1 mediated through DUB-dependent deubiquitination of STING and TBK1 leading to suppression of cGAS-STING and RIG-I-MAVS signaling. Public Library of Science 2023-02-21 /pmc/articles/PMC9983872/ /pubmed/36802409 http://dx.doi.org/10.1371/journal.ppat.1011186 Text en © 2023 Lui et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lui, Wai-Yin
Bharti, Aradhana
Wong, Nok-Hei Mickey
Jangra, Sonia
Botelho, Michael G.
Yuen, Kit-San
Jin, Dong-Yan
Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title_full Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title_fullStr Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title_full_unstemmed Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title_short Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1
title_sort suppression of cgas- and rig-i-mediated innate immune signaling by epstein-barr virus deubiquitinase bplf1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9983872/
https://www.ncbi.nlm.nih.gov/pubmed/36802409
http://dx.doi.org/10.1371/journal.ppat.1011186
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