2024
The West Nile virus genome harbors essential riboregulatory elements with conserved and host-specific functional roles
Huston N, Tsao L, Brackney D, Pyle A. The West Nile virus genome harbors essential riboregulatory elements with conserved and host-specific functional roles. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2312080121. PMID: 38985757, PMCID: PMC11260092, DOI: 10.1073/pnas.2312080121.Peer-Reviewed Original ResearchConceptsWest Nile virus genomeWest Nile virusPositive-sense RNA virusesFunctional roleArthropod cell linesRiboregulatory elementsGenome foldingFlaviviral genomeRNA genomeIncreasing global threatVirus genomeGenomeRNA virusesStructural homologyHost-dependentSecondary structureLack of effective therapeuticsFunctional validationLocked nucleic acidStructural insightsRNA drugsCell linesArthropod-borneNucleic acidsAntisense locked nucleic acidNanoparticle Retinoic Acid-Inducible Gene I Agonist for Cancer Immunotherapy
Wang-Bishop L, Wehbe M, Pastora L, Yang J, Kimmel B, Garland K, Becker K, Carson C, Roth E, Gibson-Corley K, Ulkoski D, Krishnamurthy V, Fedorova O, Richmond A, Pyle A, Wilson J. Nanoparticle Retinoic Acid-Inducible Gene I Agonist for Cancer Immunotherapy. ACS Nano 2024, 18: 11631-11643. PMID: 38652829, PMCID: PMC11080455, DOI: 10.1021/acsnano.3c06225.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsTumor microenvironmentLipid nanoparticlesBreast cancerResponse to ICIResponse to immune checkpoint inhibitorsInfiltration of CD8<sup>+</sup>Models of triple-negative breast cancerCD4<sup>+</sup> T cellsInhibition of tumor growthTriple-negative breast cancerRIG-IIonizable lipid nanoparticlesLung metastatic burdenIncrease tumor immunogenicityBreast tumor microenvironmentSignaling in vitroACTLA-4Immunogenic melanomaCheckpoint inhibitorsTumor immunogenicityImmunotherapeutic modalitiesCancer immunotherapyMetastatic burdenAPD-1
2022
The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures
Wan H, Adams RL, Lindenbach BD, Pyle AM. The In Vivo and In Vitro Architecture of the Hepatitis C Virus RNA Genome Uncovers Functional RNA Secondary and Tertiary Structures. Journal Of Virology 2022, 96: e01946-21. PMID: 35353000, PMCID: PMC9044954, DOI: 10.1128/jvi.01946-21.Peer-Reviewed Original ResearchConceptsSecondary structure mapRNA genomeRNA structureTertiary structureProtein-coding genesPositive-strand RNA virusesRegulatory RNA structuresFull-length structureHCV RNA genomeValuable model systemRNA structural motifsSecondary structural elementsEvolutionary functional analysisLife cycleVirus life cycleCellular contextCorresponding transcriptsImportant human pathogenLong RNAsGenomeSame RNAGenomic RNAComprehensive atlasFunctional analysisFunctional importanceDe novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report
Gandhi S, Klein J, Robertson AJ, Peña-Hernández MA, Lin MJ, Roychoudhury P, Lu P, Fournier J, Ferguson D, Mohamed Bakhash SAK, Catherine Muenker M, Srivathsan A, Wunder EA, Kerantzas N, Wang W, Lindenbach B, Pyle A, Wilen CB, Ogbuagu O, Greninger AL, Iwasaki A, Schulz WL, Ko AI. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report. Nature Communications 2022, 13: 1547. PMID: 35301314, PMCID: PMC8930970, DOI: 10.1038/s41467-022-29104-y.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionVirologic responsePersistent SARS-CoV-2 infectionResistance mutationsPre-treatment specimensB-cell deficiencyRemdesivir resistanceRemdesivir therapyViral sheddingCase reportAntiviral agentsPatientsCombinatorial therapyInfectionTherapyWhole-genome sequencingTreatmentImportance of monitoringDe novo emergenceFold increaseRNA-dependent RNA polymeraseNovo emergencePotential benefitsMutationsIndolent
2021
Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi
Liu T, Pyle AM. Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi. Nucleic Acids Research 2021, 49: 12422-12432. PMID: 34850132, PMCID: PMC8643640, DOI: 10.1093/nar/gkab1077.Peer-Reviewed Original ResearchConceptsGroup II intronsSelf-splicing group II intronsPathogenic fungiDrug targetsAntifungal drug targetsSelf-splicing intronsHuman pathogenic fungiMitochondrial genomeNear-physiological conditionsPromising drug targetProtein cofactorsStriking diversitySequence dataIntronsFungal pathogensInformatics searchBioinformatics workflowsFungiDimorphic fungusStructural signaturesPathogensGenomeCofactorDiversityTargetNoncoding RNAs: biology and applications—a Keystone Symposia report
Cable J, Heard E, Hirose T, Prasanth KV, Chen L, Henninger JE, Quinodoz SA, Spector DL, Diermeier SD, Porman AM, Kumar D, Feinberg MW, Shen X, Unfried JP, Johnson R, Chen C, Wilusz JE, Lempradl A, McGeary SE, Wahba L, Pyle AM, Hargrove AE, Simon MD, Marcia M, Przanowska RK, Chang HY, Jaffrey SR, Contreras LM, Chen Q, Shi J, Mendell JT, He L, Song E, Rinn JL, Lalwani MK, Kalem MC, Chuong EB, Maquat LE, Liu X. Noncoding RNAs: biology and applications—a Keystone Symposia report. Annals Of The New York Academy Of Sciences 2021, 1506: 118-141. PMID: 34791665, PMCID: PMC9808899, DOI: 10.1111/nyas.14713.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsKeystone Symposia reportPotential drug targetsRNA biologyHuman transcriptomeEpigenetic modificationsKeystone eSymposiumNoncoding RNAsCell signalingBasic biologyDrug targetsRNABiologyDisease mechanismsNucleotidesSpeciesTranscriptomeImportant roleRNAsTranscriptionSymposium reportSignalingTranslationRoleTargetSingle-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes
Ravindra NG, Alfajaro MM, Gasque V, Huston NC, Wan H, Szigeti-Buck K, Yasumoto Y, Greaney AM, Habet V, Chow RD, Chen JS, Wei J, Filler RB, Wang B, Wang G, Niklason LE, Montgomery RR, Eisenbarth SC, Chen S, Williams A, Iwasaki A, Horvath TL, Foxman EF, Pierce RW, Pyle AM, van Dijk D, Wilen CB. Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes. PLOS Biology 2021, 19: e3001143. PMID: 33730024, PMCID: PMC8007021, DOI: 10.1371/journal.pbio.3001143.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionSARS-CoV-2Human bronchial epithelial cellsInterferon-stimulated genesCell state changesAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCell tropismCoronavirus 2 infectionCoronavirus disease 2019Onset of infectionCell-intrinsic expressionCourse of infectionAir-liquid interface culturesHost-viral interactionsBronchial epithelial cellsSingle-cell RNA sequencingCell typesIL-1Disease 2019Human airwaysDevelopment of therapeuticsDrug AdministrationViral replicationComprehensive in vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms
Huston NC, Wan H, Strine MS, de Cesaris Araujo Tavares R, Wilen CB, Pyle AM. Comprehensive in vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms. Molecular Cell 2021, 81: 584-598.e5. PMID: 33444546, PMCID: PMC7775661, DOI: 10.1016/j.molcel.2020.12.041.Peer-Reviewed Original ResearchConceptsRNA structureSecondary structureRNA virusesSARS-CoV-2 RNA genomeNovel regulatory motifsSingle-nucleotide resolutionDownstream functional analysisRNA drug targetsPositive-sense RNA virusesGenome architectureGenomic structureEvolutionary analysisRegulatory motifsSARS-CoV-2 genomeViral life cycleRNA genomeFunctional analysisGenomeDrug targetsPrimer designInfected cellsViral RNADepth structural analysisLife cycleΒ-coronavirus
2020
Sequencing and Structure Probing of Long RNAs Using MarathonRT: A Next-Generation Reverse Transcriptase
Guo LT, Adams RL, Wan H, Huston NC, Potapova O, Olson S, Gallardo CM, Graveley BR, Torbett BE, Pyle AM. Sequencing and Structure Probing of Long RNAs Using MarathonRT: A Next-Generation Reverse Transcriptase. Journal Of Molecular Biology 2020, 432: 3338-3352. PMID: 32259542, PMCID: PMC7556701, DOI: 10.1016/j.jmb.2020.03.022.Peer-Reviewed Original ResearchConceptsLong RNA moleculesLong RNAsRNA moleculesRNA base modificationsGroup II intronsMutational profilingTranscriptome compositionRNA metabolismRNA researchBase modificationsPrimer extensionTool enzymeDiverse aspectsMixed populationEnzymeReverse transcriptionRNAStructural complexityReverse transcriptaseProfilingTranscriptase enzymeIntronsTranscriptionSmall-Molecule Antagonists of the RIG‑I Innate Immune Receptor
Rawling DC, Jagdmann GE, Potapova O, Pyle AM. Small-Molecule Antagonists of the RIG‑I Innate Immune Receptor. ACS Chemical Biology 2020, 15: 311-317. PMID: 31944652, DOI: 10.1021/acschembio.9b00810.Peer-Reviewed Original ResearchConceptsInnate immune systemRIG-I receptorRole of RIGSmall molecule antagonistsPotent RIGAutoimmune disordersAntimicrobial therapyRange of diseasesImmune systemInterferon responseVertebrate innate immune systemImmune receptorsReceptorsNew drug design strategiesAntagonistRNA virusesDrug design strategiesCOPD
2019
RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling
Ren X, Linehan MM, Iwasaki A, Pyle AM. RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling. Cell Reports 2019, 29: 3807-3815.e3. PMID: 31851914, DOI: 10.1016/j.celrep.2019.11.052.Peer-Reviewed Original ResearchConceptsRNA moleculesRIG-I activationBase pair sequenceHost RNA moleculesViral RNA moleculesRIG-I recognitionMolecular basisRNA variantsRNA targetsPair sequenceHuman cellsBase pairsImmune receptorsMechanisms of evasionTerminal base pairsLigand affinityWhole animalInterferon responseDeadly pathogenRNA therapeuticsMarburg virusCellsOverhangMoleculesSignaling
2016
Transcriptome analysis of human cumulus cells reveals hypoxia as the main determinant of follicular senescence
Molinari E, Bar H, Pyle AM, Patrizio P. Transcriptome analysis of human cumulus cells reveals hypoxia as the main determinant of follicular senescence. Molecular Human Reproduction 2016, 22: 866-876. PMID: 27268410, PMCID: PMC4986421, DOI: 10.1093/molehr/gaw038.Peer-Reviewed Original ResearchConceptsRNA sequencingHuman cumulus cellsCumulus cellsGEO accession numberHypoxia stress responseWhole transcriptome analysisTranscriptome analysisSomatic cellsEmbryonic developmentBioinformatics toolsGene pathwaysSpecific molecular findingsAccession numbersCell agingMolecular mechanismsStress responseVasculature developmentGenetic differencesSAMPLES/MATERIALSGenetic platformMolecular pathwaysReproductive potentialCAMP turnoverGenesSenescence
2015
HOTAIR Forms an Intricate and Modular Secondary Structure
Somarowthu S, Legiewicz M, Chillón I, Marcia M, Liu F, Pyle AM. HOTAIR Forms an Intricate and Modular Secondary Structure. Molecular Cell 2015, 58: 353-361. PMID: 25866246, PMCID: PMC4406478, DOI: 10.1016/j.molcel.2015.03.006.Peer-Reviewed Original ResearchConceptsFunctional secondary structureFundamental cellular processesSecondary structureProtein-binding motifsProtein-binding domainsGroup II intronsMetastasis suppressor geneSecondary structure elementsCellular processesPhylogenetic analysisLncRNA moleculesEpidermal developmentChemical probingMolecular mechanismsSuppressor geneCancer progressionStructural organizationKey playersLncRNA HOTAIRHOTAIRStructure elementsRNAHomogenous formReceptor activatorIntrons
2014
The RIG-I ATPase core has evolved a functional requirement for allosteric stabilization by the Pincer domain
Rawling DC, Kohlway AS, Luo D, Ding SC, Pyle AM. The RIG-I ATPase core has evolved a functional requirement for allosteric stabilization by the Pincer domain. Nucleic Acids Research 2014, 42: 11601-11611. PMID: 25217590, PMCID: PMC4191399, DOI: 10.1093/nar/gku817.Peer-Reviewed Original ResearchConceptsATPase coreRetinoic acid-inducible gene IAcid-inducible gene INon-self RNASeries of mutationsActivity of RIGMetazoan cellsHelicase coreAllosteric controlTerminal domainPattern recognition receptorsAlpha-helixBiophysical analysisGene IAllosteric stabilizationType I interferonEnzymatic activityRecognition receptorsViral RNAStructural studiesRNAI interferonAdjacent domainsDomainImportant roleThe Linker Region of NS3 Plays a Critical Role in the Replication and Infectivity of Hepatitis C Virus
Kohlway A, Pirakitikulr N, Ding SC, Yang F, Luo D, Lindenbach BD, Pyle AM. The Linker Region of NS3 Plays a Critical Role in the Replication and Infectivity of Hepatitis C Virus. Journal Of Virology 2014, 88: 10970-10974. PMID: 24965468, PMCID: PMC4178846, DOI: 10.1128/jvi.00745-14.Peer-Reviewed Original Research
2013
Parts, assembly and operation of the RIG-I family of motors
Rawling DC, Pyle AM. Parts, assembly and operation of the RIG-I family of motors. Current Opinion In Structural Biology 2013, 25: 25-33. PMID: 24878341, PMCID: PMC4070197, DOI: 10.1016/j.sbi.2013.11.011.Peer-Reviewed Original ResearchDefining the functional determinants for RNA surveillance by RIG‐I
Kohlway A, Luo D, Rawling DC, Ding SC, Pyle AM. Defining the functional determinants for RNA surveillance by RIG‐I. EMBO Reports 2013, 14: 772-779. PMID: 23897087, PMCID: PMC3790051, DOI: 10.1038/embor.2013.108.Peer-Reviewed Original ResearchConceptsMelanoma differentiation-associated gene 5Robust ATPase activityDuplex RNA substrateMinimal functional unitATPase activityRetinoic acid-inducible geneInnate immune machineryAcid-inducible geneRNA surveillanceDifferentiation-associated gene 5RNA substratesIntracellular RNA sensorsDuplex RNARNA complexRNA targetsGene 5RNA virusesDistinct conformationsRNA sensorsDsRNA complexImmune machineryRNA duplexesInterferon responseFunctional determinantsFunctional units
2002
The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding
Pang PS, Jankowsky E, Planet PJ, Pyle AM. The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding. The EMBO Journal 2002, 21: 1168-1176. PMID: 11867545, PMCID: PMC125889, DOI: 10.1093/emboj/21.5.1168.Peer-Reviewed Original ResearchConceptsRNA unwindingHelicase activityDNA helicase activityCytoplasmic RNA virusesProcessive DNA helicaseImportant drug targetsReplicative DNA intermediatesNS3 helicase activityViral NS3 proteinDNA helicaseDuplex unwindingPhylogenetic analysisReplicative roleProcessive helicaseDNA intermediatesHelicaseHost DNARNA virusesRNA activityRNA replicationDrug targetsNS3 proteinUnwindingCentral roleDNAmda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties
Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB. mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 637-642. PMID: 11805321, PMCID: PMC117358, DOI: 10.1073/pnas.022637199.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAmino Acid SequenceAnimalsApoptosisCell DifferentiationCell DivisionCloning, MolecularDEAD-box RNA HelicasesDNA, ComplementaryGrowth InhibitorsHumansInterferon Type IInterferon-Induced Helicase, IFIH1MelanomaMolecular Sequence DataRecombinant ProteinsRNA HelicasesRNA, Double-StrandedSequence Homology, Amino AcidTumor Cells, CulturedTumor Stem Cell AssayConceptsRNA-dependent ATPase activityCaspase recruitment domainHelicase motifsHuman melanoma cellsRecruitment domainRNA helicase motifsRNA-dependent ATPaseMDA-5RNA helicase domainPutative RNA helicaseMelanoma cellsEarly response genesATPase activityProtein kinase C activationGrowth-suppressive propertiesMelanoma differentiation-associated gene 5Appropriate pharmacological manipulationKinase C activationHypothetical proteinsRNA helicaseHelicase domainDifferentiation-associated gene 5Mediator of IFNSubtraction hybridizationMda-5 expression