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 degradationInductionComplement 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 hosts