African Swine Fever Virus MGF-505-7R Negatively Regulates cGAS–STING-Mediated Signaling Pathway

Li, Dan; Yang, Wei; Li, Lulu; Li, Pan; Ma, Zhao; Zhang, Jing; Qi, Xiaolan; Ren, Jingjing; Ru, Yi; Niu, Qingli; Liu, Zhijie; Liu, Xiangtao

doi:10.4049/jimmunol.2001110

Cited by 116 publications

(127 citation statements)

References 38 publications

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“…The pMGF505-7R/pA528R from MGF505 inhibits both IRF3 and ISRE promoter activation [ 43 ]. During the manuscript was being reviewed, ASFV CN/GS/2018 strain pMGF505-7R was found to promote ULK1-mediated STING degradation to negatively regulate IFN production [ 22 ]. In this study, we also found that nearly all members of pMGFs can inhibit IFN-β production, and pMGF505-7R shows the strongest inhibitory effect ( Fig 3B ).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, attenuated ASFV strains which lack genes from MGF360 and MGF505 are more susceptible to type I IFNs [ 21 ]. Recently, a study shows that ASFV-encoded pMGF505-7R negatively regulates cGAS-STING Pathway by promoting ULK1-mediated STING degradation [ 22 ]. These results suggest that inhibition of the production of type I IFNs is an important strategy utilized by ASFV to evade host immune response and maintain infection.…”

Section: Introductionmentioning

confidence: 99%

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pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

et al. 2021

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Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

et al. 2021

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“…IL-15 (but not IL-18) has been shown to confer NKG2Dmediated cytolytic function upon memory CD8 + T cells (Tough et al, 1999;Bastidas et al, 2014). NKG2D in CD8 + T cells can mediate costimulatory activity in the presence of TCR engagement (Groh et al, 2001: Jamieson et al, 2002Roberts et al, 2001;Maasho et al, 2005). However, NKG2D signaling can also occur in the absence of TCR engagement (Lanier et al, 2015).…”

Section: The Induction Of Natural Killer Receptors and Function In T Cells By Cytokinesmentioning

confidence: 99%

Induction of T Cell Senescence by Cytokine Induced Bystander Activation

Abbas

Akbar

2021

Front. Aging

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As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

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“…ASFV is a cytoplasmic dsDNA virus and mainly activates DNA-sensing cGAS-STING signaling pathway (16). Recently, two studies reported that ASFV pDP96R and pA528R (MGF505-7R) suppress cGAS-STING pathway mediated production of IFNs and proinflammatory cytokines by targeting TBK1/IKK and STING, respectively (17,18). However, the question whether the cGAS-STING pathway is suppressed by other ASFV viral proteins still persist.…”

Section: The Asfv Ps273r Protein Significantly Inhibits Cgas-sting Signaling Activitymentioning

confidence: 99%

The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε

Luo

Jiang

et al. 2021

Preprint

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African swine fever virus (ASFV), a large and complex cytoplasmic double-stranded DNA virus, has developed multiple strategies to evade the antiviral innate immune responses. Cytosolic DNA arising from invading ASFV is mainly detected by the cyclic GMP-AMP synthase (cGAS) and then triggers a series of innate immune responses to prevent virus invasion. However, the immune escape mechanism of ASFV remains to be fully clarified. The pS273R of ASFV is a member of the SUMO-1-specific protease family and is crucial for valid virus replication. In this study, we identified pS273R as a suppressor of cGAS-STING pathway mediated type I interferon (IFN) production by ASFV genomic open reading frame screening. The pS273R was further confirmed as an inhibitor of IFN production as well as its downstream antiviral genes in cGAS-STING pathway. Mechanistically, pS273R greatly decreased the cGAS-STING signaling by targeting IKKe but not TBK1 and pS273R was found to disturb the interaction between IKKe and STING through its interaction with IKKe. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which may affect the IKKe sumoylation state required for the interaction with STING. In summary, our results revealed for the first time that pS273R acts as an obvious negative regulator of cGAS-STING pathway by targeting IKKϵ via its enzymatic activity, which shows a new immune evasion mechanism of ASFV.

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African Swine Fever Virus MGF-505-7R Negatively Regulates cGAS–STING-Mediated Signaling Pathway

Cited by 116 publications

References 38 publications

pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

Induction of T Cell Senescence by Cytokine Induced Bystander Activation

The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε

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