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

Luo, Jia; Zhang, Jiajia; Ni, Jinghua; Jiang, Sheng; Xia, Nengwen; Guo, Yiwen; Shao, Qi; Cao, Qi; Zheng, Wanglong; Chen, Nanhua; Zhang, Quan; Chen, Hongjun; Chen, Qing; Zhu, Hongfei; Meurens, François; Zhu, Jianzhong

doi:10.1080/21505594.2022.2065962

Cited by 32 publications

(18 citation statements)

References 41 publications

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“…However, the molecular mechanism of ASFV modulating the cGAS-STING pathway has not been fully elucidated. Thus, we have analyzed the effects of whole genomic open reading frames (ORFs) from ASFV China 2018/1 on the activation of cGAS-STING pathway (25), and found that p17 was able to inhibit the porcine cGAS-STING mediated IFN signaling. Our work pointed the role of p17 in the immune evasion and help understand the ASFV pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

et al. 2022

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African swine fever virus (ASFV) encodes more than 150 proteins, which establish complex interactions with the host for the benefit of the virus in order to evade the host’s defenses. However, currently, there is still a lack of information regarding the roles of the viral proteins in host cells. Here, our data demonstrated that ASFV structural protein p17 exerts a negative regulatory effect on cGAS-STING signaling pathway and the STING signaling dependent anti-HSV1 and anti-VSV functions. Further, the results indicated that ASFV p17 was located in ER and Golgi apparatus, and interacted with STING. ASFV p17 could interfere the STING to recruit TBK1 and IKKϵ through its interaction with STING. It was also suggested that the transmembrane domain (amino acids 39–59) of p17 is required for interacting with STING and inhibiting cGAS-STING pathway. Additionally, with the p17 specific siRNA, the ASFV induced IFN-β, ISG15, ISG56, IL-6 and IL-8 gene transcriptions were upregulated in ASFV infected primary porcine alveolar macrophages (PAMs). Taken together, ASFV p17 can inhibit the cGAS-STING pathway through its interaction with STING and interference of the recruitment of TBK1 and IKKϵ. Our work establishes the role of p17 in the immune evasion and thus provides insights on ASFV pathogenesis.

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Section: Introductionmentioning

confidence: 99%

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

et al. 2022

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“…Probably for this reason, ASFV encodes several genes devoted to the control of IFN-I, mainly within the MGF360 and MGF505/530 multigene families, aiming to evade host defenses (Afonso et al, 2004;Correia et al, 2013;O'Donnell et al, 2015;Reis et al, 2016). Not only that, but many other ASFV genes not belonging to these multigene families have also been involved in the modulation of the immune response, such as A238L, which inhibits the expression of TNF-alpha, the transcriptional co-activator p300 or iNOS (Granja et al, 2006a,b;Granja et al, 2008Granja et al, , 2009; I329L protein that impair the activation of IFN-β and CCL5 by inhibiting TLR3 (de Oliveira et al, 2011) or the proteins DP96R (Wang et al, 2018), S273R (Luo et al, 2022) and E120R (Liu et al, 2021), among others, which counteract IFN-I production by inhibiting cGAS-STING pathway.…”

Section: Discussionmentioning

confidence: 99%

African swine fever virus ubiquitin-conjugating enzyme pI215L inhibits IFN-I signaling pathway through STAT2 degradation

et al. 2023

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African swine fever virus (ASFV) is the causative agent of one of the most lethal diseases affecting domestic pig and wild boar, which is endangering the swine industry due to its rapid expansion. ASFV has developed different mechanisms to evade the host immune response, including inhibition of type I IFN (IFN-I) production and signaling, since IFN-I is a key element in the cellular antiviral response. Here, we report a novel mechanism of evasion of the IFN-I signaling pathway carried out by the ASFV ubiquitin-conjugating enzyme pI215L. Our data showed that pI215L inhibited IFN-stimulated response element (ISRE) activity and the consecutive mRNA induction of the IFN-stimulated genes ISG15 and IFIT1 through the ubiquitination and proteasomal degradation of STAT2. Additionally, by immunofluorescence, co-immunoprecipitation and nucleus-cytoplasm fractionation approaches, we have confirmed the interaction and colocalization of STAT2 and pI215L, in ectopic experiments and during ASFV infection. Moreover, expression of the catalytic mutant (I215L-C85A) did not inhibit the induction of ISG15 and IFIT1, nor the activity of ISRE. Furthermore, we confirmed that STAT2 degradation by pI215L is dependent on its catalytic activity, since expression of the pI215L-C85A mutant did not affect STAT2 levels, compared to the wild-type protein. Yet, our data reveal that the interaction of pI215L with STAT2 does not require the integrity of its catalytic domain since the pI215L-C85A mutant co-immunoprecipitates with STAT2. All these findings reveal, for the first time, the involvement of E2-ubiquitin-conjugating enzyme activity of pI215L in the immune response modulation.

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“…Except for the negative modulation on PTMs of TBK1, late-expressed pA137R can also mediate the autophagosome and lysosome-dependent degradation of TBK1 to block the STING-IRF3 signaling pathway [ 52 ]. Of note, ASFV-encoded pS273R, a member of the SUMO-1-specific protease family, can affect the SUMOylation of inhibitor of nuclear factor kappa-B kinase ε (Ikkε) by its catalytic activity [ 53 ]. Ikkε, a homolog of TBK1, seems to involve in the activation of STING-IRF3 signaling pathway although the mechanism is not fully clear [ 54 ].…”

Section: Suppression Of Ifn-i Production and Ifn-induced Antiviral Re...mentioning

confidence: 99%

Antagonisms of ASFV towards Host Defense Mechanisms: Knowledge Gaps in Viral Immune Evasion and Pathogenesis

Zhu

Deng³

et al. 2023

Viruses

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African swine fever (ASF) causes high morbidity and mortality of both domestic pigs and wild boars and severely impacts the swine industry worldwide. ASF virus (ASFV), the etiologic agent of ASF epidemics, mainly infects myeloid cells in swine mononuclear phagocyte system (MPS), including blood-circulating monocytes, tissue-resident macrophages, and dendritic cells (DCs). Since their significant roles in bridging host innate and adaptive immunity, these cells provide ASFV with favorable targets to manipulate and block their antiviral activities, leading to immune escape and immunosuppression. To date, vaccines are still being regarded as the most promising measure to prevent and control ASF outbreaks. However, ASF vaccine development is delayed and limited by existing knowledge gaps in viral immune evasion, pathogenesis, etc. Recent studies have revealed that ASFV can employ diverse strategies to interrupt the host defense mechanisms via abundant self-encoded proteins. Thus, this review mainly focuses on the antagonisms of ASFV-encoded proteins towards IFN-I production, IFN-induced antiviral response, NLRP3 inflammasome activation, and GSDMD-mediated pyroptosis. Additionally, we also make a brief discussion concerning the potential challenges in future development of ASF vaccine.

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

Cited by 32 publications

References 41 publications

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

African swine fever virus ubiquitin-conjugating enzyme pI215L inhibits IFN-I signaling pathway through STAT2 degradation

Antagonisms of ASFV towards Host Defense Mechanisms: Knowledge Gaps in Viral Immune Evasion and Pathogenesis

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