2021
The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes
Ranjan K, Hedl M, Abraham C. The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2013500118. PMID: 34353900, PMCID: PMC8364215, DOI: 10.1073/pnas.2013500118.Peer-Reviewed Original ResearchMeSH KeywordsCytokinesHumansImmunity, InnateInflammatory Bowel DiseasesIntestinesMacrophagesMyeloid CellsNF-kappa BNod2 Signaling Adaptor ProteinPolymorphism, Single NucleotideReceptor-Interacting Protein Serine-Threonine Kinase 2Receptors, Pattern RecognitionToll-Like Receptor 2Toll-Like Receptor 4UbiquitinationUbiquitin-Protein LigasesConceptsPattern recognition receptorsE3 ubiquitin ligase activityStimulation of PRRsAntimicrobial reactive oxygen speciesMultiple pattern recognition receptorsLoss of functionLigase activityReactive nitrogen speciesComplex assemblyIntestinal myeloid cellsReactive oxygen speciesAutophagy pathwayDownstream signalingRNF186Bacterial clearanceRisk variantsRecognition receptorsHuman macrophagesOxygen speciesInnate immunityInflammatory bowel diseaseNitrogen speciesMicrobial clearanceSpeciesMyeloid cells
2017
Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes
Lahiri A, Hedl M, Yan J, Abraham C. Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nature Communications 2017, 8: 15614. PMID: 28593945, PMCID: PMC5472760, DOI: 10.1038/ncomms15614.Peer-Reviewed Original ResearchMeSH KeywordsBacteriaCells, CulturedCrohn DiseaseCytokinesElectron Transport Complex IIExtracellular Signal-Regulated MAP KinasesHumansImmunity, InnateIntracellular Signaling Peptides and ProteinsJNK Mitogen-Activated Protein KinasesMacrophagesNF-kappa BNod2 Signaling Adaptor ProteinP38 Mitogen-Activated Protein KinasesProteinsReactive Oxygen SpeciesReceptors, Pattern RecognitionRNA InterferenceRNA, Small InterferingSuccinate DehydrogenaseConceptsBacterial clearanceCytokine secretionDisease risk variantsReceptor-induced responsesMyeloid-derived cellsNOD2 stimulationRecognition receptorsHuman macrophagesSuccinate dehydrogenaseMtROS productionMitochondrial ROS productionROS productionOutcomesSDH activityMacrophagesSecretionFunctional consequencesClearanceLACC1PRRImportant contributorCellsDisease-associated lociReceptors
2015
MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation
Lahiri A, Hedl M, Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 10461-10466. PMID: 26240347, PMCID: PMC4547281, DOI: 10.1073/pnas.1501752112.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAutophagyCaspase 1CytokinesEnzyme ActivationGene Expression RegulationGenetic Predisposition to DiseaseGenotypeHomeostasisHumansInflammationInflammatory Bowel DiseasesLeukocytes, MononuclearLigandsMacrophagesMonocytesProtein Structure, TertiaryProtein Tyrosine Phosphatases, Non-ReceptorRisk FactorsRNA, Small InterferingSignal TransductionToll-Like ReceptorsConceptsPattern recognition receptorsCaspase-1 activationInflammatory bowel diseaseMTMR3 expressionReceptor-induced signalingHost pattern recognition receptorsCytokine secretionMultiple genetic lociPhosphatase domainMicrobial interactionsGenetic lociMTMR3Undefined roleAutophagyIL-1β secretionRecognition receptorsHuman macrophagesAutophagy levelEnhanced autophagyProtein 3Bowel diseaseCytokine productionRisk polymorphismsRisk allelesAltered functionA TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion
Hedl M, Abraham C. A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Gut 2015, 65: 1799. PMID: 26215868, PMCID: PMC5106344, DOI: 10.1136/gutjnl-2014-308922.Peer-Reviewed Original ResearchConceptsCaspase-8 activationMonocyte-derived macrophagesAutocrine IL-1βIL-18 secretionHost-microbial interactionsCytokine secretionHuman monocyte-derived macrophagesHuman myeloid cellsMyeloid cellsCaspase-1Intestinal myeloid cellsPattern recognition receptorsOligomerisation domainIL-1βPrimary human myeloid cellsReal-time PCRFunctional consequencesTpl2NFκB signalingRecognition receptorsRNA expressionIntestinal immune homeostasisERKMyeloid-derived cellsJNK