African Swine Fever Virus pI215L Inhibits Type I Interferon Signaling by Targeting Interferon Regulatory Factor 9 for Autophagic Degradation

Li, Liang; Fu, Jiyang; Li, Jixuan; Guo, Shibang; Chen, Qichao; Zhang, Hongjie; Liu, Zhankui; Tan, Chen; Chen, Huanchun; Wang, Xiangru

doi:10.1128/jvi.00944-22

Cited by 28 publications

(19 citation statements)

References 74 publications

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“…Ectopic expression of pI215L inhibits ISRE promoter activity and mRNA induction of the IFN-I-stimulated genes ISG15 and IFIT1 upon IFN-I stimulation, being this inhibition pI215L-dose-dependent and strictly relies on the E2 activity. In line with this, a recently published paper by Li et al (2022) showed that pI215L inhibited IFN-I signaling by degrading IRF9, implying the I215L protein as a modulator of the JAK/STAT pathway. However, the intrinsic pI215L E2-ubiquitin-conjugating function was not shown to be involved in the inhibition of the IFN-I pathway.…”

Section: Discussionsupporting

confidence: 56%

“…pI215L has been implicated in the modulation of the innate immune response by preventing IFN-I production through inhibition of NF-κB and AP1 (Barrado-Gil et al, 2021) and by regulating the cGAS-STING pathway through the inhibition of TBK1 phosphorylation (Huang et al, 2021). Recently, it has been described that I215L modulates IFN-I signaling through degradation of IRF9 via the autophagosomal/lysosomal pathway (Li et al, 2022). However, no studies involving ubiquitin-conjugating activity of pI215L as a negative regulator of the IFN-I production or IFN-I signaling have been reported.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

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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“…For instance, the V protein of Newcastle disease virus inhibited IFN signaling by promoting ubiquitination-dependent degradation of MAVS via RNF5 [34]. African swine fever virus pI215L protein recruited RNF138 to reduce K63-linked ubiquitination of TBK1, resulting in the inhibition of IFN production [35]. The NNV CP is responsible for host innate immune evasion, however its exact evasion mechanisms are not well characterized.…”

Section: Discussionmentioning

confidence: 99%

Ring-finger protein 34 facilitates nervous necrosis virus evading antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation

Zhang

Chen

Yao

et al. 2022

Preprint

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Ubiquitination enables a tight control on host immune responses, and could be hijacked by viruses for their survival. Here, we found fish pathogen nervous necrosis virus (NNV) recruited an E3 ubiquitin ligase ring finger protein 34 (RNF34) to inhibit RLRs-mediated interferons (IFN) response via ubiquitinating TBK1 and IRF3. RNF34 was found greatly enhanced NNV replication and prevented IFN production. Mechanically, RNF34 targeted TBK1 and IRF3 of different fish species for K27 and K48-linked ubiquitination degradation, which in turn diminishing TBK1-induced translocation of IRF3 from cytoplasm to nucleus. Furthermore, NNV capsid protein (CP) directly bind with different fishes RNF34, and CP-induced TBK1 and IRF3 degradation and IFN suppression depended on RNF34. Our findings demonstrated a novel mechanism by which NNV CP evaded host innate immunity via RNF34, and provided a potential drug target for the control of NNV infection.

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“…ASFV pI215L (UBCv1) can interfere with the formation of ISG3 in both ubiquitin-conjugating enzyme-activity-independent and dependent manners. ASFV pI215L (UBCv1) can interact with IRF9 and mediate the degradation of IRF9 via autophagy-lysosome pathway, which is independent of its ubiquitin-conjugating enzyme activity [ 85 ]. Additionally, ASFV pI215L (UBCv1) can also mediate the degradation of STAT2 via ubiquitin-proteasome pathway, which is dependent on its ubiquitin-conjugating enzyme activity [ 86 ].…”

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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African Swine Fever Virus pI215L Inhibits Type I Interferon Signaling by Targeting Interferon Regulatory Factor 9 for Autophagic Degradation

Cited by 28 publications

References 74 publications

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

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

Ring-finger protein 34 facilitates nervous necrosis virus evading antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation

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

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