2023
The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko N, Ahmed O, Lam T, Wang W, Shen H, Somlo S, Caplan M. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nature Communications 2023, 14: 1790. PMID: 36997516, PMCID: PMC10063565, DOI: 10.1038/s41467-023-37449-1.Peer-Reviewed Original ResearchConceptsPolycystin-1Nicotinamide nucleotide transhydrogenaseTerminal tailCystic phenotypeAutosomal dominant polycystic kidney diseaseCyst cell proliferationC-terminal domainAmino acid residuesLethal monogenic disorderC-terminal cleavageNucleotide transhydrogenaseAcid residuesMitochondrial functionTransgenic expressionPKD1 geneRedox stateShort fragmentsCell proliferationMonogenic disordersDominant polycystic kidney diseasePolycystic kidney diseaseGene therapy strategiesProteinPhenotypeFragments
2022
Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR
Sempou E, Kostiuk V, Zhu J, Cecilia Guerra M, Tyan L, Hwang W, Camacho-Aguilar E, Caplan M, Zenisek D, Warmflash A, Owens N, Khokha M. Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR. Nature Communications 2022, 13: 6681. PMID: 36335122, PMCID: PMC9637099, DOI: 10.1038/s41467-022-34363-w.Peer-Reviewed Original ResearchConceptsPluripotent cellsAdult tissue homeostasisCell fate commitmentDifferentiated cell fatesLeft-right patterningPluripotent embryonic cellsHuman embryonic stem cellsTemporal transcriptome analysisGene regulatory networksExpense of differentiationEmbryonic stem cellsGerm layer differentiationMembrane depolarizationFate commitmentPluripotent stateCell fateTranscriptome analysisRegulatory networksMyogenic lineageEmbryonic developmentTissue homeostasisDifferentiated fateEmbryonic cellsCandidate genesPluripotency
2021
β3 adrenergic receptor as potential therapeutic target in ADPKD
Schena G, Carmosino M, Chiurlia S, Onuchic L, Mastropasqua M, Maiorano E, Schena FP, Caplan MJ. β3 adrenergic receptor as potential therapeutic target in ADPKD. Physiological Reports 2021, 9: e15058. PMID: 34676684, PMCID: PMC8531837, DOI: 10.14814/phy2.15058.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseΒ3-ARΒ3-adrenergic receptorTherapeutic targetKidney/body weight ratioΒ3-AR levelSympathetic nerve activityBody weight ratioType 2 receptorCyst-lining epithelial cellsDominant polycystic kidney diseaseRenal tubular cellsNovel therapeutic targetCyclic AMP accumulationPotential therapeutic targetVasopressin type 2 receptorHuman renal tissuePolycystic kidney diseaseFluid-filled cystsADPKD mouse modelNerve activityKidney functionKidney diseaseRenal parenchymaHealthy controls
2020
Chloride channels regulate differentiation and barrier functions of the mammalian airway
He M, Wu B, Ye W, Le DD, Sinclair AW, Padovano V, Chen Y, Li KX, Sit R, Tan M, Caplan MJ, Neff N, Jan YN, Darmanis S, Jan LY. Chloride channels regulate differentiation and barrier functions of the mammalian airway. ELife 2020, 9: e53085. PMID: 32286221, PMCID: PMC7182432, DOI: 10.7554/elife.53085.Peer-Reviewed Original ResearchConceptsChloride channelsSingle-cell RNA sequencingNon-redundant roleCellular programsCellular landscapeRNA sequencingMolecular eventsEpithelial progenitorsGenetic inactivationMucosal barrierAirway barrier functionDevelopmental landscapeBarrier functionAbnormal mucociliary clearanceMammalian airwaysProtective mucosal barrierAirway mucosal barrierHuman fetal developmentPrimary targetAirway formationAirway disordersAirway diseaseAirway defectsMucus obstructionMouse airwaysA cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling
Padovano V, Mistry K, Merrick D, Gresko N, Caplan MJ. A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling. Cellular Signalling 2020, 72: 109634. PMID: 32283256, PMCID: PMC7269866, DOI: 10.1016/j.cellsig.2020.109634.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin proteinsG proteinsPolycystin-1 proteinProtein maturationTerminal tailObligate stepBiological pathwaysProtein cleavagePhysiological functionsProteolytic siteProteinPathological consequencesAutosomal dominant polycystic kidney diseaseTraffickingDominant polycystic kidney diseasePolycystic kidney diseasePrimary functionCleavageRegulationMaturationGenesMitochondriaValuable insightsPathwayMechanisms involved in AMPK-mediated deposition of tight junction components to the plasma membrane
Wu J, Rowart P, Jouret F, Gassaway BM, Rajendran V, Rinehart J, Caplan MJ. Mechanisms involved in AMPK-mediated deposition of tight junction components to the plasma membrane. American Journal Of Physiology - Cell Physiology 2020, 318: c486-c501. PMID: 31913699, PMCID: PMC7099514, DOI: 10.1152/ajpcell.00422.2019.Peer-Reviewed Original ResearchConceptsJunction assemblyPlasma membranePhospho-defective mutantsEpithelial junction assemblyMDCK renal epithelial cellsProtein kinase activationJunction-associated proteinsRenal epithelial cellsActive GTPEpithelial polarizationTight junction componentsZO-1 localizationAMPK activationKinase activationKey regulatorAfadinAMPKImportant regulatorJunction componentsProtein zonula occludens-1Par3Epithelial cellsTight junction protein zonula occludens-1RegulatorAssembly
2019
Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask)
Schena G, Caplan MJ. Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask). Cells 2019, 8: 357. PMID: 30995798, PMCID: PMC6523418, DOI: 10.3390/cells8040357.Peer-Reviewed Original ResearchConceptsNovel pharmacological approachesCurrent clinical practiceNovel therapeutic targetAR signalingΒ3-ARPharmacological approachesOcular diseasesTherapeutic targetAdrenergic receptorsClinical practiceFindings translateClinical areasCellular modelSuitable animalAppealing targetInter-species differencesDiseaseReceptors
2018
Newly synthesized polycystin‐1 takes different trafficking pathways to the apical and ciliary membranes
Gilder AL, Chapin HC, Padovano V, Hueschen CL, Rajendran V, Caplan MJ. Newly synthesized polycystin‐1 takes different trafficking pathways to the apical and ciliary membranes. Traffic 2018, 19: 933-945. PMID: 30125442, PMCID: PMC6237641, DOI: 10.1111/tra.12612.Peer-Reviewed Original ResearchConceptsPolycystin-1Ciliary deliveryBrefeldin AApical deliveryRenal epithelial cellsN-terminal fragmentPolycystin-2LLC-PK1 renal epithelial cellsDifferent trafficking pathwaysTrans-Golgi networkApical membraneEpithelial cellsCultured epithelial cellsTrafficking pathwaysTransmembrane proteinGolgi compartmentPrimary ciliaC-terminal fragmentCiliary membraneC-terminusAutocatalytic cleavageDistinct pathwaysIncubating cellsCell membraneAutosomal dominant polycystic kidney diseasePolycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Merrick D, Mistry K, Wu J, Gresko N, Baggs JE, Hogenesch JB, Sun Z, Caplan MJ. Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Human Molecular Genetics 2018, 28: 16-30. PMID: 30215740, PMCID: PMC6298236, DOI: 10.1093/hmg/ddy322.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBone DevelopmentCell DifferentiationE1A-Associated p300 ProteinGene Expression RegulationGenes, RegulatorHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsKidneyModels, AnimalMorpholinosOsteoblastsOsteogenesisPolycystic Kidney, Autosomal DominantTrans-ActivatorsTranscription FactorsTranscriptional Coactivator with PDZ-Binding Motif ProteinsTRPP Cation ChannelsZebrafishZebrafish ProteinsConceptsC-terminal tailCurly tail phenotypePolycystin-1Tail phenotypeTranscriptional coactivator TAZMessenger RNARunx2 transcriptional activityBone developmentTranscription factor Runx2Co-regulatory proteinsPkd1 mutant miceEssential coactivatorTranscriptional pathwaysTranscriptional activityOsteoblast differentiationKey mechanistic linkTAZPhysiological functionsPKD1 geneMechanistic linkRunx2MorpholinoPhenotypeMutant miceAutosomal dominant polycystic kidney diseaseMetabolism and mitochondria in polycystic kidney disease research and therapy
Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nature Reviews Nephrology 2018, 14: 678-687. PMID: 30120380, DOI: 10.1038/s41581-018-0051-1.Peer-Reviewed Original ResearchConceptsPolycystic kidney disease 1Polycystin-1Autosomal dominant polycystic kidney diseaseHallmark of ADPKDFluid-filled renal cystsPolycystin proteinsADPKD cellsPKD genesMolecular mechanismsOxidative phosphorylationCell metabolismRegulatory rolePhysiological functionsADPKD pathogenesisEnergy metabolismPotential therapeutic targetMonogenic diseasesEnergy productionMitochondriaDominant polycystic kidney diseasePolycystic kidney diseaseTherapeutic targetMutationsAlternative pathwayMetabolismImplications of AMPK in the Formation of Epithelial Tight Junctions
Rowart P, Wu J, Caplan MJ, Jouret F. Implications of AMPK in the Formation of Epithelial Tight Junctions. International Journal Of Molecular Sciences 2018, 19: 2040. PMID: 30011834, PMCID: PMC6073107, DOI: 10.3390/ijms19072040.Peer-Reviewed Original ResearchConceptsTJ assemblyPlasma membraneAMPK activationUbiquitous serine/threonine kinaseSerine/threonine kinaseBaso-lateral domainTight junctionsImplication of AMPKSelective paracellular permeabilityCell polarityThreonine kinaseDisruption of TJsProtein kinaseEnergy sensorTJ regulationΓ subunitMembrane componentsZO-1 distributionAssembly/AMPKEpithelial tight junctionsEssential roleZonula occludensKinaseEpithelial cells
2017
The secretory pathway at 50: a golden anniversary for some momentous grains of silver
Matlin KS, Caplan MJ. The secretory pathway at 50: a golden anniversary for some momentous grains of silver. Molecular Biology Of The Cell 2017, 28: 229-232. PMID: 28082520, PMCID: PMC5231891, DOI: 10.1091/mbc.e16-07-0508.Peer-Reviewed Original ResearchConceptsSecretory pathwayBiosynthetic machineryMembrane protein trafficSpecialized cell typesCell's biosynthetic machineryModern cell biologyProtein trafficCell biologyCell typesMorphological methodologiesPathological consequencesPathwayMachineryCentral paradigmBiologyDynamic natureSecretoryCulmination of decadesCellsAdaptationDiscovery
2016
The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function
Padovano V, Kuo IY, Stavola LK, Aerni HR, Flaherty BJ, Chapin HC, Ma M, Somlo S, Boletta A, Ehrlich BE, Rinehart J, Caplan MJ. The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Molecular Biology Of The Cell 2016, 28: 261-269. PMID: 27881662, PMCID: PMC5231895, DOI: 10.1091/mbc.e16-08-0597.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Cellular oxygen-sensing pathwaysMitochondrial functionOxygen-sensing pathwayBroad physiological rolesProlyl hydroxylase domainCellular energy metabolismPolycystin complexIon channel complexEndoplasmic reticulum CaPC1 expressionSubcellular localizationHydroxylase domainMitochondrial CaER CaNovel rolePhysiological roleEnergy metabolismChannel complexChannel activityPolycystinsAutosomal dominant polycystic kidney diseaseReticulum CaDominant polycystic kidney diseaseNewly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments
Stoops EH, Hull M, Caplan MJ. Newly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments. Traffic 2016, 17: 1272-1285. PMID: 27649479, PMCID: PMC5123909, DOI: 10.1111/tra.12449.Peer-Reviewed Original ResearchConceptsApical early endosomesPlasma membrane proteinsPolarized epithelial cellsApical recycling endosomesDistinct trafficking pathwaysSNAP-tag systemBasolateral membrane domainsProtein sortingApical proteinsRecycling endosomesTrafficking pathwaysGolgi networkProtein trafficMembrane domainsMembrane proteinsEarly endosomesPlasma membraneInitial traffickingEndosomesApical membraneProteinGp135Same compartmentEpithelial cellsTraffickingInvestigation of peanut oral immunotherapy with CpG/peanut nanoparticles in a murine model of peanut allergy
Srivastava KD, Siefert A, Fahmy TM, Caplan MJ, Li XM, Sampson HA. Investigation of peanut oral immunotherapy with CpG/peanut nanoparticles in a murine model of peanut allergy. Journal Of Allergy And Clinical Immunology 2016, 138: 536-543.e4. PMID: 27130858, DOI: 10.1016/j.jaci.2016.01.047.Peer-Reviewed Original ResearchConceptsPeanut oral immunotherapyOral peanut challengesPeanut-specific immunotherapyPeanut allergyOral immunotherapyPeanut challengeSymptom scoresRecall responsesMurine modelSplenocyte culturesHistamine levelsPeanut-specific serum IgEC3H/HeJ miceIFN-γ levelsPlasma histamine levelsVehicle control animalsCytokine recall responsesLower symptom scoresBody temperatureCurrent clinical approachesOral sensitizationWeekly gavageIgG2a levelsSublingual immunotherapySerum IgEArtificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy
Siefert AL, Caplan MJ, Fahmy TM. Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy. Biomaterials 2016, 97: 85-96. PMID: 27162077, PMCID: PMC5999034, DOI: 10.1016/j.biomaterials.2016.03.039.Peer-Reviewed Original ResearchConceptsMonophosphoryl lipid APathogen-associated molecular patternsT cell responsesToll-like receptorsAntigen-specific T-helper 1Antigen-specific T cell responsesCell responsesMolecular patternsAntibody-mediated responsesT helper 1Model antigen ovalbuminBacterial pathogen-associated molecular patternsCytokine profileAntigen-loaded nanoparticlesTLR ligandsCellular immunityHelper 1Vaccine efficacyAntigen ovalbuminVaccine platformImmune responseNanoparticulate vaccinesLipid AOvalbuminCpG
2015
The periciliary ring in polarized epithelial cells is a hot spot for delivery of the apical protein gp135
Stoops EH, Hull M, Olesen C, Mistry K, Harder JL, Rivera-Molina F, Toomre D, Caplan MJ. The periciliary ring in polarized epithelial cells is a hot spot for delivery of the apical protein gp135. Journal Of Cell Biology 2015, 211: 287-294. PMID: 26504168, PMCID: PMC4621837, DOI: 10.1083/jcb.201502045.Peer-Reviewed Original ResearchConceptsPrimary ciliaSurface proteinsTrans-Golgi networkPolarized epithelial cellsApical surface proteinsSNAP-tag systemBasolateral plasma membraneCell surface proteinsEpithelial cellsApical proteinsPericiliary regionGolgi networkPolarized traffickingCarrier vesiclesProtein deliveryPlasma membraneApical membraneProteinGp135Basolateral membraneCiliaMembraneHot spotsCellsTraffickingDual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin
Farr GA, Hull M, Stoops EH, Bateson R, Caplan MJ. Dual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin. Molecular Biology Of The Cell 2015, 26: 4401-4411. PMID: 26424804, PMCID: PMC4666135, DOI: 10.1091/mbc.e14-09-1385.Peer-Reviewed Original ResearchConceptsTrans-Golgi networkPlasma membraneE-cadherinK-ATPasePolarized MDCK epithelial cellsPost-Golgi traffickingCell surfacePolarized epithelial cellsEpithelial cellsMDCK epithelial cellsDistinct trafficking routesBiosynthetic traffickingCarrier vesiclesSecretory pathwayMembrane proteinsSurface deliveryBasolateral domainMost proteinsTrafficking routesGolgi complexTemperature blockTraffickingProteinMembraneCellsKnockdown of ezrin causes intrahepatic cholestasis by the dysregulation of bile fluidity in the bile duct epithelium in mice
Hatano R, Akiyama K, Tamura A, Hosogi S, Marunaka Y, Caplan MJ, Ueno Y, Tsukita S, Asano S. Knockdown of ezrin causes intrahepatic cholestasis by the dysregulation of bile fluidity in the bile duct epithelium in mice. Hepatology 2015, 61: 1660-1671. PMID: 25311759, PMCID: PMC6083834, DOI: 10.1002/hep.27565.Peer-Reviewed Original ResearchConceptsBile duct proliferationIntrahepatic cholestasisDuct proliferationExtensive bile duct proliferationBiliary HCO3- concentrationImmortalized mouse cholangiocytesSevere intrahepatic cholestasisAquaporin-1Cystic fibrosis transmembrane conductance regulatorBile duct epitheliumBile acid accumulationSurface expressionBile duct morphologyReduced functional expressionPeriportal fibrosisBile ductInflammatory cellsBile flowCholestatic diseasePeriductular fibrosisBiliary epitheliumHepatic disordersAnion exchanger 2Useful modelVirus infectionPolycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability
Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, Contreras-Ferrat A, Fernández C, Jiang N, Luo X, Caplan MJ, Somlo S, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation 2015, 131: 2131-2142. PMID: 25888683, PMCID: PMC4470854, DOI: 10.1161/circulationaha.114.013537.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBiomarkersCalcium Channels, L-TypeCardiomegalyCells, CulturedFibrosisHypertrophyHypotonic SolutionsMaleMechanotransduction, CellularMiceMice, KnockoutMyocytes, CardiacProtein Interaction MappingProtein StabilityProtein Structure, TertiaryRatsRats, Sprague-DawleyRecombinant Fusion ProteinsRNA InterferenceStress, MechanicalTRPP Cation ChannelsConceptsL-type calcium channel activityCalcium channel activityNeonatal rat ventricular myocytesRat ventricular myocytesKnockout miceVentricular myocytesChannel activityMechanical stretchNeonatal rat ventricular myocyte hypertrophyProtein levelsVentricular myocyte hypertrophyL-type Ca2G protein-coupled receptor-like proteinPolycystin-1Channel protein levelsCyclic mechanical stretchControl miceInterstitial fibrosisStress-induced activationCardiac massMechanical stress-induced activationCardiac functionRNAi-dependent knockdownCardiac hypertrophyLittermate controls