Defining the functional interface between the ER and flaviviruses
Defining the functional interface between the ER and flaviviruses
批准号:
10401436
负责人:
Sara Cherry
金额:
$61.39万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-20 至 2024-05-31
关键词:
AffectAmericasAntiviral AgentsBiochemicalBiologyCRISPR/Cas technologyCellsCellular StressCellular biologyComplementComplexCytoplasmDengueDengue InfectionDevelopmentDiamondEndoplasmic ReticulumEndosomesFlavivirusFlavivirus InfectionsGenerationsGenesGeneticGenetic ScreeningGenomeGlycoproteinsGoalsGrantHealthHumanImmunologyInfectionInsectaIntegration Host FactorsJapanese EncephalitisLaboratoriesLife Cycle StagesMass Spectrum AnalysisMembraneMolecularNeural Cell Adhesion Molecule L1Pathway interactionsPeptide Signal SequencesPolyproteinsProcessProductionProtein GlycosylationProtein SecretionProteinsRNARNA VirusesRNA interference screenRNA replicationRoleShapesSiteStressStructural ProteinTherapeuticToxic effectTranslatingTranslationsUntranslated RNAVaccinesVector-transmitted infectious diseaseViralViral PathogenesisViral ProteinsViral Structural ProteinsVirionVirusVirus DiseasesVirus-like particleWest Nile virusYellow FeverYellow fever virusZIKAZIKV infectionZika Virusclinical developmentcombatemerging pathogengenome-wideimmunogenicityin vivoinnovationlipid biosynthesislipid metabolismmulticatalytic endopeptidase complexnovel therapeuticspolypeptideprotein complexprotein foldingresponsesignal peptidasesmall moleculeubiquitin ligasevirology
中文摘要
黄病毒是一种相关的正链包膜RNA病毒属
英文摘要
Flaviviruses are a genus of related positive-stranded enveloped RNA viruses that significantly
impact human health, including dengue (DENV), Zika (ZIKV). West Nile (WNV), Japanese
encephalitis (JEV), and yellow fever (YFV) viruses. The discovery of host factors critical for viral
infection reveals new aspects of cell biology, intricate virus-host relationships, and potential
targets for antiviral therapeutics. After entering cells and fusing in the acidified endosome, the
flavivirus RNA genome penetrates into the cytoplasm and is then translated into a polyprotein and
processed at the endoplasmic reticulum (ER). In addition to utilizing many functions of the ER for
protein production, flaviviruses extensively remodel ER membranes to create a niche for RNA-
dependent RNA replication. The ER also is the site for flavivirus assembly, which enables the
production and secretion of new infectious viruses. Thus, the ER serves as a central point for
orchestrating many of the essential steps in the flavivirus infection life cycle. Despite this, little is
known about the host factors and molecular mechanisms at the ER that are required for optimal
translation and processing of the viral proteins or for the assembly of the replication niche. We
recently have performed several genetic screens to identify important components in this process.
Our genome-wide RNAi screen with WNV in insect cells validated 18 genes associated with ER
biology that promote infection. Our CRISPR/Cas9 gene-editing screen in human cells with WNV
also identified 12 ER-associated genes. These screens converged on ER-resident proteins as
being critical for WNV infection and included genes associated with ER-translocation and signal
peptide processing, ER-associated degradation (ERAD), protein glycosylation, protein folding and
lipid metabolism. Indeed, infection of WNV, ZIKV, JEV, DENV, and YFV all required specific
subunit components of the host signal peptidase complex (SPCS) for processing of the viral
polyprotein, the production of viral glycoproteins and thus generation of nascent virions. The
objective of this proposal is to define the molecular mechanisms by which flaviviruses use specific
ER-associated host proteins to promote viral translation, polyprotein processing, RNA replication,
and/or assembly. Aim 1 will define the mechanism by which the ER translocon promotes
polyprotein translation and processing while Aim 2 will dissect the role of ER-associated decay
(ERAD) in promoting flavivirus replication. Our long-term goal is to determine the mechanisms by
which flaviviruses exploit the ER for their replication, as this will reveal both fundamental aspects
of virology as well as new avenues for antiviral therapeutics.
期刊论文(7)
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DOI:
10.7554/elife.55500
发表时间:
2020-12-03
期刊:
eLife
影响因子:
7.7
作者:
[Thompson MG, Dittmar M, Mallory MJ, Bhat P, Ferretti MB, Fontoura BM, Cherry S, Lynch KW]
通讯作者:
Lynch KW
DOI:
10.1126/sciimmunol.abi9007
发表时间:
2021-05-18
期刊:
Science immunology
影响因子:
24.8
作者:
[]
通讯作者:
DOI:
10.1016/j.virol.2020.01.010
发表时间:
2020-01
期刊:
Virology
影响因子:
3.7
作者:
[W. Palmer;M. Dittmar;B. Gordesky-Gold;J. Hofmann;S. Cherry]
通讯作者:
W. Palmer;M. Dittmar;B. Gordesky-Gold;J. Hofmann;S. Cherry
DOI:
10.1128/mbio.01194-23
发表时间:
2023-08-31
期刊:
mBio
影响因子:
6.4
作者:
[]
通讯作者:
RNA Biology in Viral Infection.
病毒感染中的 RNA 生物学。
DOI:
10.1016/j.semcdb.2020.12.001
发表时间:
2021
期刊:
Seminars in cell & developmental biology
影响因子:
7.3
作者:
[]
通讯作者:
Development and validation of antivirals against Flaviviruses
-
批准号:10514328
-
项目类别:
-
资助金额:$489.76万
-
财政年份:2022
-
负责人:Sara Cherry
-
依托单位:
Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.
-
批准号:10551893
-
项目类别:
-
资助金额:$40.63万
-
财政年份:2020
-
负责人:Sara Cherry
-
依托单位:
Small Molecule Screening to Identify Novel Sars-CoV-2 Therapeutics
-
批准号:10223018
-
项目类别:
-
资助金额:$33.6万
-
财政年份:2020
-
负责人:Sara Cherry
-
依托单位:
Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.
-
批准号:10326823
-
项目类别:
-
资助金额:$40.63万
-
财政年份:2020
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:10468096
-
项目类别:
-
资助金额:$50.61万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
Small Molecule Screening to Identify Novel Sars-CoV-2 Therapeutics
-
批准号:10239297
-
项目类别:
-
资助金额:$22.48万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:9917158
-
项目类别:
-
资助金额:$52.1万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:10686406
-
项目类别:
-
资助金额:$50.59万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:10673509
-
项目类别:
-
资助金额:$24.38万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:10222526
-
项目类别:
-
资助金额:$50.64万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
The role of pattern recognition and autophagy in innate anti-bunyaviral immunity
-
批准号:10023159
-
项目类别:
-
资助金额:$50.55万
-
财政年份:2019
-
负责人:Sara Cherry
-
依托单位:
Defining the functional interface between the ER and flaviviruses
-
批准号:10180892
-
项目类别:
-
资助金额:$61.39万
-
财政年份:2018
-
负责人:Sara Cherry
-
依托单位:
Antiviral immunity in the gut: how the intestinal epithelium and microbiota regulate infection
-
批准号:9179594
-
项目类别:
-
资助金额:$39.43万
-
财政年份:2015
-
负责人:Sara Cherry
-
依托单位:
Defining the determinants on the alphavirus receptor NRAMP required for virus bin
-
批准号:8426761
-
项目类别:
-
资助金额:$24.0万
-
财政年份:2013
-
负责人:Sara Cherry
-
依托单位:
Defining the determinants on the alphavirus receptor NRAMP required for virus bin
-
批准号:8606813
-
项目类别:
-
资助金额:$20.0万
-
财政年份:2013
-
负责人:Sara Cherry
-
依托单位:
Dissecting the alphavirus entry receptor NRAMP
-
批准号:8677683
-
项目类别:
-
资助金额:$46.59万
-
财政年份:2012
-
负责人:Sara Cherry
-
依托单位:
Dissecting the alphavirus entry receptor NRAMP
-
批准号:8501353
-
项目类别:
-
资助金额:$43.79万
-
财政年份:2012
-
负责人:Sara Cherry
-
依托单位:
Dissecting the alphavirus entry receptor NRAMP
-
批准号:8296800
-
项目类别:
-
资助金额:$48.09万
-
财政年份:2012
-
负责人:Sara Cherry
-
依托单位:
Indentification of Cellular Pathways Involvedin Rift Valley Fever Virus Infection
-
批准号:8233376
-
项目类别:
-
资助金额:$30.51万
-
财政年份:2011
-
负责人:Sara Cherry
-
依托单位:
Indentification of Cellular Pathways Involvedin Rift Valley Fever Virus Infection
-
批准号:7670063
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项目类别:
-
资助金额:$30.0万
-
财政年份:2009
-
负责人:Sara Cherry
-
依托单位:
海外基金