Negative regulation of human antiviral RNAi by PACT
PACT 对人类抗病毒 RNAi 的负调控
基本信息
- 批准号:10667112
- 负责人:
- 金额:$ 7.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-23 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAffinityAntiviral AgentsBindingBiogenesisCaenorhabditis elegansCell Differentiation processCell divisionCell physiologyDNA Sequence AlterationDefectDevelopmentDouble-Stranded RNAFBXW7 geneGene ExpressionGenesGenomeHumanHuman ActivitiesIn VitroInfectionInfection preventionInvertebratesMammalsMediatingMicroRNAsMolecularMusNCOA6 geneNematodaNewborn InfantPhysiologicalPlantsProcessProductionProteinsRNA InterferenceRNA VirusesRegulationResearchSmall Interfering RNAStructureTherapeuticTranscriptTransgenesViralViral Load resultViral PhysiologyVirusVirus DiseasesVirus ReplicationWorkantiviral immunitycell growthds RNA-Binding Proteinsfungusimprovedin vivoinsightknockout genenovel therapeutic interventionreconstitutionrecruitstem cellstreatment strategyviral RNA
项目摘要
PROJECT SUMMARY
Small interfering RNAs (siRNAs) processed from virus-produced double-stranded RNA
(dsRNA) mediate potent antiviral immunity, often termed as antiviral RNA interference (RNAi), in
fungi, plants and invertebrates. Antiviral RNAi is often initiated by dicer proteins which chop viral
dsRNAs into siRNAs. Argonaut (AGO) proteins recruit dicer-produced siRNAs and use them as
sequence guide to identify and destroy viral RNA transcripts with matching sequence. The destruction
of target viral transcripts is mediated by the slicer activity of AGO proteins. dsRNA binding proteins
(DRBPs) also contribute to antiviral RNAi by facilitating siRNA production or loading into AGO
proteins.
Currently, whether RNAi mediates antiviral immunity in mammals under physiological
conditions is still under hot debate. Although the antiviral activity of mammalian RNAi is active in
non-differentiated stem cells and newborn mice it becomes undetectable in differentiated cells and
fully developed mice. The fact that both dicer and the AGO protein required for siRNA production
remain functionally active in differentiated cells suggest that there is a regulatory mechanism that
actively suppresses the antiviral activity of mammalian RNAi in differentiated cells. Currently, how
this regulatory mechanism works remains largely unknown. Since key mammalian RNAi genes, such
as those encoding dicer and Ago2, are required for the biogenesis or function of miRNAs, which
regulate essential cell differentiation and division, it is impossible to knock out these genes to study the
antiviral function of mammalian RNAi without causing cell growth arrest or lethality.
By co-delivery of human dicer and Ago2, one of the human Ago proteins with slicer activity,
the PI’s lab successfully reconstituted human antiviral RNAi in C. elegans. Importantly, the antiviral
activity is further enhanced in the presence of a human TRBP transgene but appears to be suppressed
in the presence of a human PACT transgene. Both TRBP and PACT are dsRNA-binding proteins
sharing similar domain structure. Previous in vitro studies have demonstrated that whereas TRBP
facilitates the processing of dsRNA by dicer PACT seems to inhibit dicer processing of dsRNA. These
observations together with our finding suggest that TRBP and PACT conversely regulate the antiviral
activity of mammalian RNAi and PACT may dominate the regulation, leading to suppressed antiviral
activity under physiological conditions. Here we propose to study the negative regulation of human
antiviral RNAi by PACT in C. elegans. Findings from the proposed research may not only allow us to
gain insight into the mechanism by which mammalian antiviral RNAi is regulated in differentiated
cells but also facilitate the development of novel therapeutic strategies for viral infection prevention.
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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Rui Lu其他文献
Rui Lu的其他文献
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