2024
Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB
Lampson B, Ramίrez A, Baro M, He L, Hegde M, Koduri V, Pfaff J, Hanna R, Kowal J, Shirole N, He Y, Doench J, Contessa J, Locher K, Kaelin W. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. Cell 2024, 187: 2209-2223.e16. PMID: 38670073, PMCID: PMC11149550, DOI: 10.1016/j.cell.2024.03.022.Peer-Reviewed Original ResearchConceptsWhole-genome CRISPR-Cas9 screenCRISPR-Cas9 screensCryoelectron microscopy studiesCell surface localizationLipopolysaccharide receptor Toll-like receptor 4OST complexToll-like receptor 4CRISPR screensNF-kBCatalytic subunitN-glycosylationActivate NF-kBBase editorsUncompetitive inhibition mechanismNGI-1Molecular mechanismsCatalytic siteLPS-treated cellsOligosaccharyltransferaseDruggable pocketSTT3AReceptor Toll-like receptor 4Drug mechanism of actionStructural studiesInflammatory signaling
2019
Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing
Klaver E, Zhao P, May M, Flanagan-Steet H, Freeze HH, Gilmore R, Wells L, Contessa J, Steet R. Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing. Disease Models & Mechanisms 2019, 12: dmm039602. PMID: 31101650, PMCID: PMC6602306, DOI: 10.1242/dmm.039602.Peer-Reviewed Original ResearchConceptsNull cellsReceptor processingEndoplasmic reticulum localizationGlycan site occupancyInsulin-like growth factor 1 receptorReceptor tyrosine kinasesGrowth factor 1 receptorFactor 1 receptorCell surface glycoproteinMutant cellsNGI-1Catalytic subunitReceptor kinaseGlycosylation statusReduced abundanceTyrosine kinaseGlycan occupancyTyrosine receptor kinaseSurface localizationInsulin receptorAbnormal glycosylationProteolytic processingFunctional consequencesCell surfaceGlycosylation
2018
Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors
Rinis N, Golden JE, Marceau CD, Carette JE, Van Zandt MC, Gilmore R, Contessa JN. Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors. Cell Chemical Biology 2018, 25: 1231-1241.e4. PMID: 30078634, PMCID: PMC6337728, DOI: 10.1016/j.chembiol.2018.07.005.Peer-Reviewed Original ResearchConceptsNGI-1Cellular unfolded protein responseMultisubunit enzyme complexN-glycan site occupancyUnfolded protein responseSubset of glycoproteinsSubunit-specific inhibitorsSecretory pathwayCatalytic subunitProtein responseEnzyme complexTarget proteinsOligosaccharyltransferasePharmacologic inhibitionGlycosylationProteinCell modelBiological effectsInhibitorsStructure-activity relationshipsSTT3BSTT3APharmacological approachesSubunitsSite occupancy
2017
A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity
Puschnik AS, Marceau CD, Ooi YS, Majzoub K, Rinis N, Contessa JN, Carette JE. A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity. Cell Reports 2017, 21: 3032-3039. PMID: 29241533, PMCID: PMC5734657, DOI: 10.1016/j.celrep.2017.11.054.Peer-Reviewed Original ResearchMeSH KeywordsAntiviral AgentsBenzamidesDengue VirusGene ExpressionGene Expression RegulationGenes, ReporterHEK293 CellsHexosyltransferasesHost-Pathogen InteractionsHumansLuciferasesMembrane ProteinsMicrobial Sensitivity TestsSignal TransductionSulfonamidesVirus ReplicationWest Nile virusYellow fever virusZika VirusConceptsAntiviral activityMosquito-borne flavivirusPromising antiviral activityYellow fever virusNGI-1Strong antiviral activityFlavivirus infectionImportant human pathogenAntiviral compoundsHost factorsViral RNA replicationWest NileFever virusDisease-relevant cell typesGlobal healthInfectionFlavivirusesViral mutantsBroad activityCell typesGenetic determinantsHuman pathogensRNA replicationRecent genetic screenTarget activity