Investigating MERS-CoV NS4b as a modulator of the host antiviral response in the nucleus
研究 MERS-CoV NS4b 作为细胞核内宿主抗病毒反应的调节剂
基本信息
- 批准号:9619001
- 负责人:
- 金额:$ 2.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2019-05-20
- 项目状态:已结题
- 来源:
- 关键词:A549Amino AcidsAntiviral AgentsAntiviral ResponseBiologicalBiological AssayBiologyCRISPR/Cas technologyCell DeathCell LineCell NucleusCellsCessation of lifeCleaved cellCo-ImmunoprecipitationsConflict (Psychology)Confocal MicroscopyCoronavirusCytoplasmDataDipeptidyl-Peptidase IVDistributional ActivityEctopic ExpressionEngineeringEnsureEnzyme-Linked Immunosorbent AssayEnzymesEpithelialExhibitsExonsFamilyGene ExpressionGenetic TranscriptionGenomeHistidineHomologous GeneHumanIRF3 geneImmune responseImportinsInfectionInterferon-betaInterferonsIntronsKineticsKnock-outLabelLinkLiteratureLiverMediatingMediator of activation proteinMessenger RNAMiddle East Respiratory Syndrome CoronavirusMolecular Biology TechniquesMurine hepatitis virusMusMutateMyeloid CellsNuclearNuclear ImportNuclear TranslocationPathogenesisPathway interactionsPhysiologicalPlayProcessProteinsPublic HealthRNARecombinantsReporterReportingResearchResearch PersonnelRibonucleasesRoleSARS coronavirusSequence HomologySevere Acute Respiratory SyndromeStainsStructural ModelsTestingTimeTrainingTranscriptTranscription ProcessViralViral ProteinsVirulentVirusVirus ReplicationWestern BlottingWorkZoonosesarmbasecareerexperimental studyheterokaryonleptomycin Bmutantnovelpathogenphosphodiesterphosphodiesterase Vpromoterreceptorreverse geneticssuccesstherapeutic targettranscriptome sequencingtransmission process
项目摘要
Project Summary
Middle East Respiratory Syndrome coronavirus (MERS-CoV/MERS) is a recently emerged zoonotic pathogen
that has caused almost 1,800 cases and over 600 deaths since its 2012 discovery. MERS is the second
virulent coronavirus to emerge in the last fifteen years, following SARS-CoV (SARS) in 2003, further
demonstrating that coronaviruses are a continuing threat to global public health. While MERS, SARS, and the
murine coronaviruses all belong to the same genus, Betacoronavirus, MERS is highly divergent from both and
its genome encodes a novel set of accessory proteins. All viruses must manipulate diverse arms of the host
antiviral response to ensure replicative success and transmission, and coronavirus accessory proteins
participate in these essential functions. Due to its novelty and divergence from previously studied
coronaviruses, the MERS accessory proteins are largely uncharacterized and lack significant sequence
homology with other known viral proteins. We have used structural modeling to identify the MERS NS4b
accessory protein as a homolog of the mouse hepatitis virus (MHV) NS2 accessory protein, which was
previously described by our lab as an antagonist of the antiviral enzyme RNase L. Both proteins are homologs
of the LigT-like 2H-phosphoesterases (2H-PEs), a large family of prokaryotic and eukaryotic proteins
characterized by 2 HxS/T catalytic motifs separated by 80-100 amino acids. NS2 is critical for MHV replication
in myeloid cells and the mouse liver, and inactivation of NS4b enzymatic activity results in RNase L activation
during MERS infection of human airway epithelial Calu-3 cells. Antagonism of RNase L by either MHV NS2 or
MERS NS4b is dependent on 2’,5’ phosphodiesterase activity mediated by the catalytic histidines. Despite the
similarity between these two proteins, our lab has identified striking differences and significant preliminary data
which, combined with reports in the literature that NS4b can antagonize expression from the interferon- β
promoter in reporter assays, suggest it has an additional function as compared to MHV NS2. Notably, whereas
MHV NS2 is exclusively cytoplasmic, MERS NS4b contains a strong, functional NLS and localizes primarily to
the nucleus. Our lab previously demonstrated that nuclear localization is completely dispensable for
antagonizing RNase L, and the NS4b NLS is conserved in all known MERS-like viruses, strongly supporting
the idea of a nuclear function. Additionally, whereas MHV NS2 cleaves only 2’-5’ linked phosphodiester bonds,
MERS NS4b cleaves both 2’-5’ and 3’-5’ linked bonds, giving it broader substrate range and the ability to
process RNA, as some prokaryotic and eukaryotic 2H-PEs are known to do. Our preliminary data strongly
suggest that NS4b post-transcriptionally processes host mRNAs associated with the antiviral response and cell
death, doing so in the nucleus through its enzymatic activity. Therefore, MERS NS4b is likely the first known
viral 2H-PE to act in the nucleus. This research may illuminate a new mechanism by which coronaviruses
interact with the host, and determine whether NS4b is a plausible therapeutic target during MERS infection.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stephen Goldstein其他文献
Stephen Goldstein的其他文献
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{{ truncateString('Stephen Goldstein', 18)}}的其他基金
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
- 批准号:
10157165 - 财政年份:2021
- 资助金额:
$ 2.36万 - 项目类别:
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
- 批准号:
10403422 - 财政年份:2021
- 资助金额:
$ 2.36万 - 项目类别:
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
- 批准号:
10640106 - 财政年份:2021
- 资助金额:
$ 2.36万 - 项目类别:
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
- 批准号:
10415466 - 财政年份:2021
- 资助金额:
$ 2.36万 - 项目类别:
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