African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation

African swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune...

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Main Authors: Lucía Barrado-Gil, Ana del Puerto, Inmaculada Galindo, Miguel Ángel Cuesta-Geijo, Isabel García-Dorival, Carlos Maluquer de Motes, Covadonga Alonso
Format: Article
Language:English
Published: MDPI AG 2021-06-01
Series:Viruses
Subjects:
Online Access:https://www.mdpi.com/1999-4915/13/6/1160
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author Lucía Barrado-Gil
Ana del Puerto
Inmaculada Galindo
Miguel Ángel Cuesta-Geijo
Isabel García-Dorival
Carlos Maluquer de Motes
Covadonga Alonso
author_facet Lucía Barrado-Gil
Ana del Puerto
Inmaculada Galindo
Miguel Ángel Cuesta-Geijo
Isabel García-Dorival
Carlos Maluquer de Motes
Covadonga Alonso
author_sort Lucía Barrado-Gil
collection DOAJ
description African swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune and inflammatory signaling. Transient overexpression of UBCv1 impaired activation of NF-κB and AP-1 transcription factors induced by several agonists of these pathways. In contrast, activation of IRF3 and ISRE signaling upon stimulation with TRIFΔRIP, cGAS/STING or RIG-I-CARD remained unaltered. Experiments aimed at mapping UBCv1 inhibitory activity indicated that this viral protein acts upstream or at the level step of IKKβ. In agreement with this, UBCv1 was able to block p65 nuclear translocation upon cytokine stimulation, a key event in NF-ĸB signaling. Additionally, A549 stably transduced for UBCv1 showed a significant decrease in the levels of NF-ĸB dependent genes. Interestingly, despite the well-defined capacity of UBCv1 to conjugate ubiquitin chains, a mutant disabled for ubiquitylation activity retained similar immunomodulatory activity as the wild-type enzyme, suggesting that the two functions are segregated. Altogether these data suggest that ASFV UBCv1 manipulates the innate immune response targeting the NF-κB and AP-1 pathways and opens new questions about the multifunctionality of this enzyme.
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spelling doaj.art-3e2d3d29d37b4ceab70384ca0aa135ad2023-11-22T00:32:03ZengMDPI AGViruses1999-49152021-06-01136116010.3390/v13061160African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB ActivationLucía Barrado-Gil0Ana del Puerto1Inmaculada Galindo2Miguel Ángel Cuesta-Geijo3Isabel García-Dorival4Carlos Maluquer de Motes5Covadonga Alonso6Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainDepartment of Microbial Sciences, School of Biosciences and Medicine, University of Surrey, Stag Hill, Guildford GU2 7XH, UKDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), Ctra. de la Coruña km 7.5, 28040 Madrid, SpainAfrican swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune and inflammatory signaling. Transient overexpression of UBCv1 impaired activation of NF-κB and AP-1 transcription factors induced by several agonists of these pathways. In contrast, activation of IRF3 and ISRE signaling upon stimulation with TRIFΔRIP, cGAS/STING or RIG-I-CARD remained unaltered. Experiments aimed at mapping UBCv1 inhibitory activity indicated that this viral protein acts upstream or at the level step of IKKβ. In agreement with this, UBCv1 was able to block p65 nuclear translocation upon cytokine stimulation, a key event in NF-ĸB signaling. Additionally, A549 stably transduced for UBCv1 showed a significant decrease in the levels of NF-ĸB dependent genes. Interestingly, despite the well-defined capacity of UBCv1 to conjugate ubiquitin chains, a mutant disabled for ubiquitylation activity retained similar immunomodulatory activity as the wild-type enzyme, suggesting that the two functions are segregated. Altogether these data suggest that ASFV UBCv1 manipulates the innate immune response targeting the NF-κB and AP-1 pathways and opens new questions about the multifunctionality of this enzyme.https://www.mdpi.com/1999-4915/13/6/1160innate immunityTLRNF-κBAP-1IFNSTING
spellingShingle Lucía Barrado-Gil
Ana del Puerto
Inmaculada Galindo
Miguel Ángel Cuesta-Geijo
Isabel García-Dorival
Carlos Maluquer de Motes
Covadonga Alonso
African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
Viruses
innate immunity
TLR
NF-κB
AP-1
IFN
STING
title African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
title_full African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
title_fullStr African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
title_full_unstemmed African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
title_short African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-κB Activation
title_sort african swine fever virus ubiquitin conjugating enzyme is an immunomodulator targeting nf κb activation
topic innate immunity
TLR
NF-κB
AP-1
IFN
STING
url https://www.mdpi.com/1999-4915/13/6/1160
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