Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

Xue, Qiao; Liu, Huisheng; Zhu, Zixiang; Yang, Fan; Xue, Qinghong; Cai, Xuepeng; Liu, Xiangtao; Zheng, Haixue

doi:10.1016/j.antiviral.2018.10.028

Cited by 35 publications

(35 citation statements)

References 29 publications

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“…In this study, we found that UBE2L6 is utilized by SVA to enhance replication via UBE2L6-mediated ubiquitination of the viral RdRp, 3D, which serves to stabilize 3D. The 3C protein of SVA has been reported to negatively regulate the innate immune response through deubiquitination, thereby promoting virus replication [ 41 ]. These results demonstrate that SVA has various strategies to utilize the host UPS to help it better proliferate in infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmid HA-Ub was kindly provided by Dr. Yingjuan Qian at the MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China. Plasmids HA-Ub-K48 (of the seven Lys residues, only K48 remained) and HA-Ub-K63 (of the seven Lys residues, only K48 remained) were kindly provided by Dr. Haixue Zheng at the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences [ 41 ]. HA-Ub was used as the backbone for construction of the HA-Ub-K48R and HA-Ub-K63R mutants.…”

Section: Methodsmentioning

confidence: 99%

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E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase

Bai

Fan

et al. 2020

PLoS Pathog

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Senecavirus A (SVA), discovered in 2002, is an emerging pathogen of swine that has since been reported in numerous pork producing countries. To date, the mechanism of SVA replication remains poorly understood. In this study, utilizing iTRAQ analysis we found that UBE2L6, an E2 ubiquitin-conjugating enzyme, is up-regulated in SVA-infected BHK-21 cells, and that its overexpression promotes SVA replication. We determined that UBE2L6 interacts with, and ubiquitinates the RNA-dependent RNA polymerase of SVA, (the 3D protein) and this ubiquitination serves to inhibit the degradation of 3D. UBE2L6-mediated ubiquitination of 3D requires a cystine at residue 86 in UBE2L6, and lysines at residues 169 and 321 in 3D. Virus with mutations in 3D (rK169R and rK321R) exhibited significantly decreased replication compared to wild type SVA and the repaired viruses, rK169R(R) and rK321R(R). These data indicate that UBE2L6, the enzyme, targets the 3D polymerase, the substrate, during SVA infection to facilitate replication.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase

Bai

Fan

et al. 2020

PLoS Pathog

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“…3C pro acts to remove both K48- and K63-linked polyubiquitin chains from multiple substrates including RIG-I, TBK1, and TNF receptor associated factor 3 (TRAF3), thereby blocking downstream antiviral gene expression. The authors also identified that the amino acid residues 48 and 160 were integral to the DUB activity and viral replication [ 64 ]. Foot-and-mouth disease (FMDV) leader proteinase (L pro ) is another PLP that inhibits both K48- and K63-linked ubiquitination in vitro and in overexpressed HEK293T cell-based assays.…”

Section: Viral Evasion Of Ubiquitin-mediated Rlr Responsesmentioning

confidence: 99%

Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Chiang

Liu

Gack

2021

Viruses

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Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.

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“…In SVA-infected cells, 3C pro interacts with MAVS, TRIF, and TANK to cleave these adaptors, leading to inhibition of TLR3-and RLRs-mediated IFNs production [55]. Moreover, SVA 3C pro has deubiquitinating activity which it uses to reduce the ubiquitination of RIG-I, TBK1, and TRAF3, thereby blocking the signal transduction cascade [56]. For FMDV, VP3 interacts with MAVS to prevent MDA5/RIG-I-MAVS complex formation.…”

Section: Disruption Of Adaptor Proteins and Their Kinasesmentioning

confidence: 99%

Innate immune evasion by picornaviruses

Zhang¹,

Paget

Wang³

et al. 2020

Eur J Immunol

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The family Picornaviridae comprises a large number of viruses that cause disease in broad spectrum of hosts, which have posed serious public health concerns worldwide and led to significant economic burden. A comprehensive understanding of the virus‐host interactions during picornavirus infections will help to prevent and cure these diseases. Upon picornavirus infection, host pathogen recognition receptors (PRRs) sense viral RNA to activate host innate immune responses. The activated PRRs initiate signal transduction through a series of adaptor proteins, which leads to activation of several kinases and transcription factors, and contributes to the consequent expression of interferons (IFNs), IFN‐inducible antiviral genes, as well as various inflammatory cytokines and chemokines. In contrast, to maintain viral replication and spread, picornaviruses have evolved several elegant strategies to block innate immune signaling and hinder host antiviral response. In this review, we will summarize the recent progress of how the members of family Picornaviridae counteract host immune response through evasion of PRRs detection, blocking activation of adaptor molecules and kinases, disrupting transcription factors, as well as counteraction of antiviral restriction factors. Such knowledge of immune evasion will help us better understand the pathogenesis of picornaviruses, and provide insights into developing antiviral strategies and improvement of vaccines.

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Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

Cited by 35 publications

References 29 publications

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase

E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase

Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Innate immune evasion by picornaviruses

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