African Swine Fever Virus A528R Inhibits TLR8 Mediated NF-κB Activity by Targeting p65 Activation and Nuclear Translocation

Liu, Xueliang; Ao, Da; Jiang, Sheng; Xia, Nengwen; Xu, Yan; Shao, Qi; Luo, Jia; Wang, Heng; Zheng, Wanglong; Chen, Nanhua; Meurens, François; Zhu, Jianzhong

doi:10.3390/v13102046

Cited by 20 publications

(19 citation statements)

References 34 publications

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“…Mechanistically, pMGF505-7R not only interacted with IKKα in the IKK complex to inhibit NF-κB activation and but also bound to NLRP3 to inhibit inflammasome formation, resulting in decreased IL-1β production. Consistent with these results, A528R can suppress the NF-κB p65 phosphorylation and nuclear translocation, and the antiviral and antibacterial activity (Liu et al, 2021), while an ASFV-MGF505-7R recombinant virus derived from ASFV HLJ/18 induced higher levels of IL-1β in PAMs compared with its parental ASFV HLJ/18 strain. Importantly, the virulence of ASFV-MGF505-7R is reduced in piglets, which may occur due to induction of higher IL-1β and IFN-I production in vivo.…”

Section: African Swine Fever Virus Pmgf505-7r Inhibits the Activation...supporting

confidence: 71%

Multifunctional pMGF505-7R Is a Key Virulence-Related Factor of African Swine Fever Virus

Huang

Zheng

et al. 2022

Front. Microbiol.

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African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), and it is an enveloped, icosahedral, double-stranded DNA virus with a genome length ranging from 170 to 193 kb. The ASFV genome contains at least five multigene families (MGFs): MGF100, MGF110, MGF300, MGF360, and MGF505 at the right and left terminal variable regions. The members of the same MGF family are most similar and have conserved sequence motifs, whereas the genetic diversity of different MGF families varies widely. MGF genes play a crucial role in determining ASFV host range, virulence and reducing early cell death post-infection. pMGF505-7R is a multifunctional protein. Recent research advances of pMGF505-7R provide a few new clues to understand the functions of pMGF505-7R either in antagonizing the induction of type I IFN production and IFN downstream signaling or in suppressing inflammatory responses by inhibition of NF-κB signaling and NLRP3 inflammasome, which may be related to ASFV infection-induced pathogenesis.

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Section: African Swine Fever Virus Pmgf505-7r Inhibits the Activation...supporting

confidence: 71%

Multifunctional pMGF505-7R Is a Key Virulence-Related Factor of African Swine Fever Virus

Huang

Zheng

et al. 2022

Front. Microbiol.

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“…For instance, DP96R of ASFV China 2018/1 was reported to negatively regulate IFN-I expression and NF-κB signaling by inhibiting both TBK1 and IKKβ ( Wang et al., 2018 ). MGF-505-7R interacts with IKKα, STING, and IRF3 and inhibits the cGAS-STING signaling pathway to block IFN-β and inhibit pro-inflammatory IFN-γ-mediated JAK-STAT1 signaling ( Li J. et al, 2021 ; Li et al, 2021a ; Li et al, 2021b ). E120R interacts with IRF3 and interferes with recruitment of IRF3 to TBK1, which in turn suppresses IRF3 phosphorylation, decreasing IFN production ( Liu H. et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…MGF-505-7R interacts with IKKα, STING, and IRF3 and inhibits the cGAS-STING signaling pathway to block IFN-β and inhibit pro-inflammatory IFN-γ-mediated JAK-STAT1 signaling ( Li J. et al, 2021 ; Li et al, 2021a ; Li et al, 2021b ). E120R interacts with IRF3 and interferes with recruitment of IRF3 to TBK1, which in turn suppresses IRF3 phosphorylation, decreasing IFN production ( Liu H. et al, 2021 ). MGF360-12L inhibits type I IFN production by blocking interactions between importin α and proteins in the NF-κB signaling pathway ( Zhuo et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…DP96R of the ASFV China 2018/1 strain is reported to negatively regulate type I IFN expression and NF-κB signaling by inhibiting both TBK1 and IKKβ ( Wang et al., 2018 ). A528R inhibits TLR8-NF-κB signaling by targeting p65 activation and nuclear translocation ( Liu X. et al., 2021 ). F317L interacts with IκB kinase β (IKKβ) and impairs NF-κB pathway activation by disrupting NF-κB activity to evade the host immune response ( Yang J. et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3

Wang

Cui

Xin

et al. 2022

Front. Cell. Infect. Microbiol.

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African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-β (IFN-β) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.

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“…A528R was also shown to inhibit NF-κB nuclear translocation. MGF505-11R was shown to inhibit the cGAS-STING signaling pathways ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Differential Effect of Deleting Members of African Swine Fever Virus Multigene Families 360 and 505 from the Genotype II Georgia 2007/1 Isolate on Virus Replication, Virulence, and Induction of Protection

Rathakrishnan

Connell

Petrovan

et al. 2022

J Virol

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African swine fever virus multigene family (MGF) 360 and 505 genes have roles in suppressing the type I interferon response and in virulence in pigs, The role of the individual genes is poorly understood. Different combinations of these genes were deleted from the virulent genotype II Georgia 2007/1 isolate. Deletion of five copies of MGF 360 genes, MGF360-10L, -11L, -12L, -13L, -14L and three copies of MGF505-1R, -2R and -3R reduced virus replication in macrophages and attenuated virus in pigs. However only 25% of the immunised pigs were protected against challenge. Deletion of MGF360-12L, -13L, -14L and MGF505-1R in combination with a negative serology marker, K145R, (GeorgiaΔK145RΔMGF(A)) reduced virus replication in macrophages and virulence in pigs since no clinical signs or virus genome in blood were observed following immunisation. Four out of six pigs were protected after challenge. In contrast, deletion of MGF360-13L, -14L, MGF505-2R, -3R and K145R (GeorgiaΔK145RΔMGF(B)), did not reduce virus replication in macrophages. Following immunisation of pigs, clinical signs were delayed but all pigs reached the humane endpoint. Deletion of genes MGF360-12L, MGF505-1R and K145R reduced replication in macrophages and attenuated virulence in pigs since no clinical signs or virus genome in blood were observed following immunisation. Thus, the deletion of MGF360-12L and MGF505-1R, in combination with K145R, was sufficient to dramatically attenuate virus infection in pigs. However only two of six pigs were protected, suggesting that deletion of additional MGF genes is required to induce a protective immune response. Deletion of MGF360-12L, but not MGF505-1R, from the GeorgiaΔK145R virus reduced virus replication in macrophages indicating that MGF360-12L was most critical for maintaining high levels of virus replication in macrophages. Importance African swine fever, has a high socio-economic impact and no vaccines to aid control. The virus (ASFV) has many genes that inhibit the host’s interferon response. These include related genes that are grouped into multigene families including MGF360 and 505. Here, we investigated which MGF360 and 505 genes were most important for viral attenuation and protection against genotype II strains circulating in Europe and Asia. We compared viruses with deletions of MGF genes. Deletion of just two MGF genes in combination with a third gene, K145R, a possible marker for vaccination, is sufficient for virus attenuation in pigs. Deletion of additional MGF360 genes was required to induce higher levels of protection. Furthermore, we showed that the deletion of MGF360-12L, combined with K145R, impairs virus replication in macrophages in culture. Our results have important implications for understanding the roles of the ASFV MGF genes and for vaccine development.

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African Swine Fever Virus A528R Inhibits TLR8 Mediated NF-κB Activity by Targeting p65 Activation and Nuclear Translocation

Cited by 20 publications

References 34 publications

Multifunctional pMGF505-7R Is a Key Virulence-Related Factor of African Swine Fever Virus

Multifunctional pMGF505-7R Is a Key Virulence-Related Factor of African Swine Fever Virus

African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3

Differential Effect of Deleting Members of African Swine Fever Virus Multigene Families 360 and 505 from the Genotype II Georgia 2007/1 Isolate on Virus Replication, Virulence, and Induction of Protection

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