African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D

Zhao, Gaihong; Li, Tingting; Liu, Xuemin; Zhang, Taoqing; Zhang, Zhaoxia; Li, Kang; Song, Jie; Zhou, Shijun; Chen, Xin; Wang, Xiao; Li, Jiangnan; Huang, Li; Li, Changyao; Bu, Zhigao; Zheng, Jun; Weng, Changjiang

doi:10.1016/j.jbc.2021.101480

Cited by 48 publications

(51 citation statements)

References 50 publications

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“…Our study presents clear and relevant evidence that pS273R protease acts as a sumoylation inhibitor and targets IKKε modification to interfere with the immune response. During revision of this paper, the work published by Zhao etc showed the pS273R exerts its protease activity to non-canonically cleave gasdermin D, disturb inflammasome-induced cell pyroptosis and promote ASFV replication [ 40 ]. Collectively, all these work explored different aspects of immune evasion by pS273R and broaden our understanding of immune evasion mechanism by ASFV.…”

Section: Discussionmentioning

confidence: 99%

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

Luo

Zhang

et al. 2022

Virulence

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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 IKKε but not TBK1, and pS273R was found to disturb the interaction between IKKε and STING through its interaction with IKKε. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which might affect the IKKε 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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Section: Discussionmentioning

confidence: 99%

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

Luo

Zhang

et al. 2022

Virulence

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“…Unlike the canonical GSDMD-N 1–279 produced by caspase-1, the GSDMD-N 1–107 is unable to induce pyroptosis. Notably, pS273R further cleaves GSDMD-N 1-279 to produce GSDMD-N 1-107 , which suppresses GSDMD-N 1-279 -induced pyroptosis to promote ASFV replication ( Zhao et al., 2021 ).…”

Section: Escape From Innate Immunitymentioning

confidence: 99%

“…Thus, effective inhibition of pS273R affects ASFV particle maturation and infectivity ( Alejo et al., 2003 ). A recent article shows that pS273R inhibits ASFV infection-induced pyroptosis to regulate inflammatory responses ( Zhao et al., 2021 ). pS273R interacts with GSDMD and then cleaves GSDMD at G107–A108 to produce a shorter N-terminal fragment of GSDMD (GSDMD-N 1–107 ).…”

Section: Escape From Innate Immunitymentioning

confidence: 99%

Regulation of antiviral immune response by African swine fever virus (ASFV)

2022

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“…Recently, Oh et al (2021) compared MA-104 to the renal-derived swine macrophages; they observed that MA-104 is less able to isolate the field virus, although both wild-type (MW039157) and cell-adapted (MW287337) ASFV genotype II strains grew efficiently in this continuous cell line [ 50 ]. This cell line was also efficiently used to study the interaction network of ASFV with host proteins [ 99 ] and to determine the mechanisms used by ASFV to evade the host innate immune responses [ 100 ].…”

Section: Monkey-derived Continuous Cell Linesmentioning

confidence: 99%

Cell Lines for the Development of African Swine Fever Virus Vaccine Candidates: An Update

2022

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African swine fever virus (ASFV) is the etiological agent of a highly lethal disease in both domestic and wild pigs. The virus has rapidly spread worldwide and has no available licensed vaccine. An obstacle to the construction of a safe and efficient vaccine is the lack of a suitable cell line for ASFV isolation and propagation. Macrophages are the main targets for ASFV, and they have been widely used to study virus–host interactions; nevertheless, obtaining these cells is time-consuming and expensive, and they are not ethically suitable for the production of large-scale vaccines. To overcome these issues, different virulent field isolates have been adapted on monkey or human continuous cells lines; however, several culture passages often lead to significant genetic modifications and the loss of immunogenicity of the adapted strain. Thus, several groups have attempted to establish a porcine cell line able to sustain ASFV growth. Preliminary data suggested that some porcine continuous cell lines might be an alternative to primary macrophages for ASFV research and for large-scale vaccine production, although further studies are still needed. In this review, we summarize the research to investigate the most suitable cell line for ASFV isolation and propagation.

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African swine fever virus cysteine protease pS273R inhibits pyroptosis by noncanonically cleaving gasdermin D

Cited by 48 publications

References 50 publications

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

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

Regulation of antiviral immune response by African swine fever virus (ASFV)

Cell Lines for the Development of African Swine Fever Virus Vaccine Candidates: An Update

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