ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes
Fang C, Manes TD, Liu L, Liu K, Qin L, Li G, Tobiasova Z, Kirkiles-Smith NC, Patel M, Merola J, Fu W, Liu R, Xie C, Tietjen GT, Nigrovic PA, Tellides G, Pober JS, Jane-wit D. ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes. Nature Communications 2019, 10: 2247. PMID: 31113953, PMCID: PMC6529429, DOI: 10.1038/s41467-019-10041-2.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsCarrier ProteinsCell LineComplement Membrane Attack ComplexCoronary VesselsDisease Models, AnimalEndosomesFemaleGraft RejectionHuman Umbilical Vein Endothelial CellsHumansIntracellular Signaling Peptides and ProteinsMembrane ProteinsMiceMice, SCIDNF-kappa BPhosphatidylinositol PhosphatesRab5 GTP-Binding ProteinsUbiquitin-Protein LigasesVasculitisConceptsNF-κB-inducing kinaseMembrane attack complexNon-canonical NF-κBNF-κBEC activationEndothelial cellsTransplant organ rejectionConnective tissue diseaseHumanized mouse modelAllograft vasculopathySynovial tissueTissue diseaseVascular inflammationOrgan rejectionPharmacologic alterationsMouse modelDependent mannerAttack complexProteasome-dependent degradationInductionAlloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-&kgr;B Signaling in Endothelial Cells
Jane-wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, Abrahimi P, Devalliere J, Moeckel G, Kulkarni S, Tellides G, Pober JS. Alloantibody and Complement Promote T Cell–Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-&kgr;B Signaling in Endothelial Cells. Circulation 2013, 128: 2504-2516. PMID: 24045046, PMCID: PMC3885874, DOI: 10.1161/circulationaha.113.002972.Peer-Reviewed Original ResearchConceptsCardiac allograft vasculopathyPanel reactive antibodyNuclear factor-κB signalingFactor-κB signalingAllograft vasculopathyT cellsEndothelial cellsMembrane attack complexAlloreactive T cell activationChronic antibody-mediated rejectionNoncanonical nuclear factorProinflammatory gene programAntibody-mediated rejectionDonor-specific antibodiesGraft endothelial cellsLate allograft lossAlloreactive T cellsAllogeneic endothelial cellsT cell activationAttack complexHuman T cellsAllograft lossHeart transplantationTransplantation patientsLesion pathogenesisComplement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomes
Jane-wit D, Surovtseva YV, Qin L, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles-Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+NIK+ signalosome on Rab5+ endosomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 9686-9691. PMID: 26195760, PMCID: PMC4534258, DOI: 10.1073/pnas.1503535112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBaculoviral IAP Repeat-Containing 3 ProteinClathrinComplement Membrane Attack ComplexCoronary VesselsEndocytosisEndosomesEnzyme StabilityFlow CytometryHuman Umbilical Vein Endothelial CellsHumansHydrazonesInhibitor of Apoptosis ProteinsMice, SCIDNF-kappa BProtein BiosynthesisProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktRab5 GTP-Binding ProteinsRNA, Small InterferingSecretory VesiclesSignal TransductionTNF Receptor-Associated Factor 3Ubiquitin-Protein LigasesConceptsNF-κB-inducing kinaseMembrane attack complexNoncanonical NF-κBGenome-wide siRNA screenComplement membrane attack complexNIK stabilizationDynamin-dependent mannerNoncanonical NF-κB signalingEndothelial cellsActive Rab5Attack complexSiRNA screenNF-κBAkt activationCytokine-mediated activationNF-κB signalingIκB kinaseSignalosomeRab5EndosomesKinaseAktInternalizationCoronary endothelial cellsActivationComplement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-γ–Primed Human Endothelium
Xie CB, Qin L, Li G, Fang C, Kirkiles-Smith NC, Tellides G, Pober JS, Jane-Wit D. Complement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-γ–Primed Human Endothelium. Circulation Research 2019, 124: 1747-1759. PMID: 31170059, PMCID: PMC6557295, DOI: 10.1161/circresaha.119.314845.Peer-Reviewed Original ResearchConceptsMembrane attack complexEndothelial cellsComplement membrane attack complexIL-1βNLRP3 inflammasomeEC immunogenicityComplement activationAntibody-mediated complement activationInflammasome assemblyComplement-mediated pathologiesRenal allograft biopsiesGraft endothelial cellsHuman coronary artery graftsLate allograft failureCoronary artery graftsT cell responsesImmune-mediated pathologyActivate endothelial cellsIL-1 receptorIL-1 synthesisIL-1β secretionNoncanonical NF-κB signalingNF-κB signalingAttack complexImmunodeficient mouse hostsA ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells
Li X, Jiang Q, Song G, Barkestani M, Wang Q, Wang S, Fan M, Fang C, Jiang B, Johnson J, Geirsson A, Tellides G, Pober J, Jane-wit D. A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells. Nature Communications 2023, 14: 3002. PMID: 37225719, PMCID: PMC10209169, DOI: 10.1038/s41467-023-38684-2.Peer-Reviewed Original ResearchConceptsEndothelial cellsInflammasome activityMembrane attack complexCaspase-1Potential therapeutic targetChronic rejectionComplement membrane attack complexTissue inflammationNLRP3 inflammasomeTissue injuryMouse modelTherapeutic targetDependent mannerInflammationAttack complexInflammasomeHuman tissuesFlightless IInhibitory associationsSkin modelRNF34Cells