Suppression of NF-κB Activity: A Viral Immune Evasion Mechanism

Deng, Liyao; Zeng, Qiurui; Wang, Mingshu; Cheng, Anchun; Jia, Renyong; Chen, Shun; Zhu, Dekang; Liu, Mafeng; Yang, Qiao; Wu, Ying; Zhao, Xinxin; Zhang, Shaqiu; Liu, Yunya; Yu, Yanling; Zhang, Ling; Chen, Xiaoyue

doi:10.3390/v10080409

Cited by 71 publications

(55 citation statements)

References 127 publications

(161 reference statements)

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“…The NF-κB pathway is activated as part of the innate response to viral infection, leading to expression of antiviral genes, and is frequently targeted for viral immune evasion 28,29 . Given the importance of this pathway it is surprising that the interplay between CHIKV infection and the NF-κB pathway is poorly understood.…”

Section: Resultsmentioning

confidence: 99%

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

Roberts

Stonehouse

Harris

2019

Preprint

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14The role of the chikungunya virus (CHIKV) non-structural protein 3 (nsP3) in the virus lifecycle 15 is poorly understood. The protein comprises 3 domains. The N-terminus is a macro domain, 16 biochemically characterised to bind both RNA and ADP-ribose, and to possess ADP-ribosyl 17 hydrolase activity -an enzymatic activity that removes ADP-ribose from mono-ADP-18 ribosylated proteins. As ADP-ribosylation is important in the signalling pathway leading to 19 activation of the transcription factor NF-кB, we sought to determine if the macro domain might 20 perturb NF-кB signalling. We first show that CHIKV infection did not induce NF-кB activation, 21 and could not block exogenous activation of the pathway via TNFα, although TNFα treatment 22 did reduce virus titres. Ectopic expression of nsP3 was able to block TNFα-mediated NF-кB 23 activation and this was dependent on the macro domain, as mutations previously shown to 24 disrupt either ADP-ribose binding or hydrolase activity lost the ability to inhibit NF-кB 25 activation. Lastly, we determined the phenotype of the macro domain mutants in the context 26 of virus infection in a range of cell types. Our data are consistent with cell-and species-27 dependent roles of the macro domain, however, these phenotypes do not correlate with the 28 ability to inhibit NF-кB activation suggesting that the macro domain plays multiple independent 29 roles in the virus lifecycle.Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family, and is increasingly 32 becoming a threat to global health. First discovered in Tanzania in 1952, CHIKV is now 33 classified into four distinct genotypes and has spread from Africa to Asia, Europe, and the 34 Americas 1 . CHIKV is transmitted by mosquitos and was previously geographically limited to 35 the distribution of the Aedes aegypti mosquito which favours tropical climates. However, 36 mutations in the E1 and E2 glycoproteins, detected in 2004, have enabled spread by the 37Aedes albopictus mosquito, which is more widely disseminated around the globe 2 . 38Infection with CHIKV causes Chikungunya fever, characterised by high fever, rash and joint 39 pain which can be debilitating and, in some cases, persistent 3 . CHIKV infection induces a 40 highly inflammatory state, inducing tissue damage 4 . In addition, individuals who have been 41 infected with CHIKV are significantly predisposed to arthritis in later life 5 . In healthy adults, 42 CHIKV is rarely fatal though the risk of death is high in infants, the elderly and the 43 immunocompromised 6 . 44The CHIKV genome is a positive-sense, single stranded (ss) RNA. It possesses a 5' cap and 45 a poly-A tail and contains two open reading frames (ORFs) 7 . The first ORF encodes for the 46 four non-structural proteins, nsP1-4, which are directly translated from the genomic RNA 8 . The 47 NF-кB pathway, and is unable to suppress exogenous activation of the pathway via TNFα 84 treatment. However, in contrast we further demonstrate that ectopic expression of nsP3 is 85 able to inhibit exogen...

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Section: Resultsmentioning

confidence: 99%

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

Roberts

Stonehouse

Harris

2019

Preprint

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“…PAKs, the key regulators in Rho GTPase signaling pathways, played a pivotal role in the US3-mediated formation of cell projections and were bound to and phosphorylated by US3 26,32 . In addition, US3 protein also regulates the innate immune response and apoptosis to promote viral replication by phosphorylating corresponding substrates 33,34 .…”

mentioning

confidence: 99%

The Pivotal Roles of US3 Protein in Cell-to-Cell Spread and Virion Nuclear Egress of Duck Plague Virus

Deng

Wang

Cheng

et al. 2020

Sci Rep

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The duck plague virus (DPV) US3 protein, a homolog of the herpes simplex virus-1 (HSV-1) US3 protein that is reported to be critical for viral replication, has been minimally studied. Therefore, to investigate the function of the DPV US3 protein, we used scarless Red recombination technology based on an infectious bacterial artificial chromosome (BAC) containing the DPV Chinese virulent strain (CHv) genome and successfully constructed and rescued a US3-deleted mutant and the corresponding revertant virus (BAC-CHv-ΔUS3 and BAC-CHv-ΔUS3R, respectively). For viral growth characteristics, compared to the parental and revertant viruses, the US3-deleted mutant showed an approximately 100-fold reduction in viral titers but no significant reduction in genome copies, indicating that the US3-deleted mutant exhibited decreased viral replication but not decreased viral DNA generation. In addition, the US3-deleted mutant formed viral plaques that were 33% smaller on average than those formed by the parental and revertant viruses, demonstrating that US3 protein affected the viral cell-tocell spread of DPV. Finally, the results of electron microscopy showed that the deletion of US3 resulted in a large number of virions accumulating in the nucleus and perinuclear space, thus blocking virion nuclear egress. In this study, we found that the DPV US3 protein played pivotal roles in viral replication by promoting viral cell-to-cell spread and virion nuclear egress, which may provide some references for research on the function of the DPV US3 protein.Duck plague, also known as duck viral enteritis (DVE), is an acute, febrile, septic disease that appears in waterfowl and is caused by duck plague virus (DPV). Duck plague spreads rapidly with high morbidity and mortality, resulting in significant economic losses in the avian industry. DPV belongs to the Alphaherpesvirinae subfamily and contains a double-stranded helical DNA consisting of a unique long (UL) region, a unique short (US) region, a unique short internal repeat (IRS) region and a unique short terminal repeat (TRS) region, thus forming the UL-IRS-US-TRS structure of the viral genome 1-3 .The characteristics of some genes of DPV have been reported. Herpesvirus genes are classified into immediate-early (IE), early (E) and late (L) genes according to their order of gene expression and thereby play different roles in viral replication. The kinetic classes of many DPV genes have been identified. DPV UL54, an IE gene, can shuttle between the nucleus and cytoplasm to regulate viral replication, and the recombinant UL54-deleted virus produced smaller viral plaque sizes and lower viral genome copies than the parental virus 4-7 . DPV UL13 is an E gene and localizes to the nucleus and cytoplasm, and knocking out UL13 impaired viral replication 8 . Most DPV genes, including US2 9 , US5 10 , US10 11 , UL16 12 , UL35 13 , UL41 14 , UL53 15 , and UL55 16 , are classified as L genes. To date, only a few proteins encoded by DPV apart from UL54 and UL13 have been studied in mutant viruses. Both ...

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“…NF-κB activation exacerbates lung in ammation caused by SARS-CoV infection, and inhibition of NF-κB signaling signi cantly reduces such in ammation and increases the survival rate of SARS-CoV-infected mice [48,49]. In addition, NF-κB is an important transcription factor that induces expression of viral genes, and inhibition of NF-κB activation is an immune evasion mechanism of SARS-CoV [50]. Therefore, we speculate that XBJ's active ingredients might interfere with the NF-κB pathway and regulate innate immunity and in ammation during viral infection to alleviate lung in ammation during COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Examining the effector mechanisms of Xuebijing Injection on COVID-19 based on network pharmacology.

Zheng

Yan

et al. 2020

Preprint

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Objective: To examine the potential effector mechanisms of Xuebijing (XBJ) on coronavirus disease 2019 (COVID-19) based on network pharmacology.Methods: We searched Chinese and international papers to obtain the active ingredients of XBJ. Then, we compiled COVID-19 disease targets from the GeneCards gene database and via literature searches. Next, we used the SwissTargetPrediction database to predict XBJ’s effector targets and map them to the abovementioned COVID-19 disease targets in order to obtain potential therapeutic targets of XBJ. Cytoscape software version 3.7.0 was used to construct a “XBJ active-compound-potential-effector target” network and protein-protein interaction (PPI) network, and then to carry out network topology analysis of potential targets. We used the ClueGO and CluePedia plugins in Cytoscape to conduct gene ontology (GO) biological process (BP) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of XBJ’s effector targets. Results: We obtained 144 potential COVID-19 effector targets of XBJ. Fourteen of these targets—glyceraldehyde 3-phosphate dehydrogenase (GAPDH), albumin (ALB), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), Caspase-3 (CASP3), signal transducer and activator of transcription 3 (STAT3), MAPK8, prostaglandin-endoperoxide synthase 2 (PTGS2), JUN, interleukin-2 (IL-2), estrogen receptor 1 (ESR1), and MAPK14—had degree values >40 and therefore could be considered key targets. They participated in extracellular signal–regulated kinase 1 and 2 (ERK1, ERK2) cascade, the T-cell receptor signaling pathway, activation of MAPK activity, cellular response to lipopolysaccharide, and other inflammation- and immune-related BPs. XBJ exerted its therapeutic effects through the renin–angiotensin system (RAS), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), MAPK, phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)–protein kinase B (Akt)–vascular endothelial growth factor (VEGF), toll-like receptor (TLR), TNF, and inflammatory-mediator regulation of transient receptor potential (TRP) signaling pathways to ultimately construct a “ingredient-target-pathway” effector network. Conclusion: The active ingredients of XBJ regulated different genes, acted on different pathways, and synergistically produced anti-inflammatory and immune-regulatory effects, which fully demonstrated the synergistic effects of different components on multiple targets and pathways. Our study demonstrated that existing studies on the pharmacological mechanisms of XBJ in the treatment of sepsis and severe pneumonia, could explain the effector mechanism of XBJ in COVID-19 treatment, and those provided a preliminary examination of the potential effector mechanism in this disease.

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Suppression of NF-κB Activity: A Viral Immune Evasion Mechanism

Cited by 71 publications

References 127 publications

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway

The Pivotal Roles of US3 Protein in Cell-to-Cell Spread and Virion Nuclear Egress of Duck Plague Virus

Examining the effector mechanisms of Xuebijing Injection on COVID-19 based on network pharmacology.

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