2023
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition
Yadavalli N, Ferguson S. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2303789120. PMID: 37487100, PMCID: PMC10400961, DOI: 10.1073/pnas.2303789120.Peer-Reviewed Original ResearchCab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning
Tran M, Tüshaus J, Kim Y, Ramazanov B, Devireddy S, Lichtenthaler S, Ferguson S, von Blume J. Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning. Traffic 2023, 24: 4-19. PMID: 36398980, PMCID: PMC9825660, DOI: 10.1111/tra.12873.Peer-Reviewed Original Research
2022
ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
Hancock-Cerutti W, Wu Z, Xu P, Yadavalli N, Leonzino M, Tharkeshwar AK, Ferguson SM, Shadel GS, De Camilli P. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. Journal Of Cell Biology 2022, 221: e202106046. PMID: 35657605, PMCID: PMC9170524, DOI: 10.1083/jcb.202106046.Peer-Reviewed Original ResearchConceptsParkinson's diseasePD pathogenesisLeucine-rich repeat kinase 2 (LRRK2) G2019S mutationCGAS-STING pathwayAccumulation of lysosomesDNA-sensing cGAS-STING pathwayImmune activationLipid profileSTING signalingG2019S mutationAutosomal recessive Parkinson's diseaseRecessive Parkinson's diseaseModel human cell linesHuman cell linesCell linesPathogenesisLate endosomes/lysosomesDiseaseVPS13CEndosomes/lysosomesCurrent studyTransfer proteinActivationCellsPathwayJIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton
Rafiq N, Lyons L, Gowrishankar S, De Camilli P, Ferguson S. JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton. Communications Biology 2022, 5: 5. PMID: 35013510, PMCID: PMC8748971, DOI: 10.1038/s42003-021-02945-x.Peer-Reviewed Original Research
2021
TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Alesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, Filippakis H, Lam HC, Shi W, Viswanathan SR, Morroni M, Ferguson SM, Henske EP. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nature Communications 2021, 12: 4245. PMID: 34253722, PMCID: PMC8275687, DOI: 10.1038/s41467-021-24499-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCarcinoma, Renal CellCell NucleusCell ProliferationFemaleGene Expression RegulationHEK293 CellsHeLa CellsHumansKidney NeoplasmsLysosomesMiceMice, Inbred NODMice, SCIDMonomeric GTP-Binding ProteinsOrganelle BiogenesisPhosphorylationPhosphoserineProtein TransportProto-Oncogene ProteinsTranscription, GeneticTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsConceptsTranscription factor EBTSC2-deficient cellsLysosome biogenesisLysosomal biogenesisDeficient cellsRapamycin complex 1TSC1/2 complexTFEB phosphorylationTuberous sclerosis complexTSC proteinsMaster regulatorBiogenesisMechanistic targetRagCCritical regulatorFolliculinPhosphorylationDependent sitesRegulatorProteinOverexpressionTSC2 mutationsCellsGTPaseMTORC1Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons
Gowrishankar S, Lyons L, Rafiq NM, Roczniak-Ferguson A, De Camilli P, Ferguson SM. Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. Molecular Biology Of The Cell 2021, 32: 1094-1103. PMID: 33788575, PMCID: PMC8351540, DOI: 10.1091/mbc.e20-06-0382.Peer-Reviewed Original ResearchConceptsAxonal transportAlzheimer's disease-related amyloid precursor proteinAmyloidogenic APP processingAmyloid precursor proteinDependence of neuronsHuman iPSCNeuronal cell biologyAPP processingAxonal lysosomesNeuronsLoss of JIP3Lysosome abundanceMovement of lysosomesPrecursor proteinCellular modelCritical regulatorStem cellsPluripotent stem cellsAβ42 peptideIPSCsLysosome transportLysosomesOverlapping rolePathology
2019
PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation
Amick J, Tharkeshwar AK, Talaia G, Ferguson SM. PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation. Journal Of Cell Biology 2019, 219: e201906076. PMID: 31851326, PMCID: PMC7039192, DOI: 10.1083/jcb.201906076.Peer-Reviewed Original ResearchConceptsC9orf72 complexAmino acidsNormal lysosome functionAmino acid-sensing mechanismAmino acid starvationMembrane of lysosomesRegulated recruitmentComplex recruitmentCationic amino acidsHeterotrimeric complexPQLC2Acid-sensing mechanismsBinding partnerC9orf72 proteinComplex abundanceLysosome functionNovel mechanismLysosomesWDR41New roleComplexesRecruitmentSMCR8AcidProteinWeak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment
Angarola B, Ferguson SM. Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment. Molecular Biology Of The Cell 2019, 30: 2750-2760. PMID: 31532697, PMCID: PMC6789162, DOI: 10.1091/mbc.e19-03-0146.Peer-Reviewed Original ResearchMeSH KeywordsAmino AcidsAnimalsChlorocebus aethiopsCOS CellsEndoplasmic ReticulumHeLa CellsHumansLysosomesMechanistic Target of Rapamycin Complex 1Monomeric GTP-Binding ProteinsMultiprotein ComplexesNeuropeptidesPrenylationRas Homolog Enriched in Brain ProteinSignal TransductionTOR Serine-Threonine KinasesConceptsMembrane interactionsC-terminal CAAX motifTransient membrane interactionsEndoplasmic reticulum localizationMTOR complex 1CAAX motifRheb GTPaseER membraneMTORC1 activationSubcellular localizationTargeting motifRhebLysosome enrichmentHuman cellsFunctional assaysTargeting mechanismStable interactionStable localizationLysosomesFurther systematic analysisMotifActivation
2017
Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology
Gowrishankar S, Wu Y, Ferguson SM. Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. Journal Of Cell Biology 2017, 216: 3291-3305. PMID: 28784610, PMCID: PMC5626538, DOI: 10.1083/jcb.201612148.Peer-Reviewed Original ResearchConceptsJNK-interacting protein 3Plaque pathologyAmyloid plaquesAxonal swellingsAmyloid precursor protein-processing enzymeAmyloidogenic amyloid precursor protein processingAmyloid precursor protein processingAlzheimer's disease (AD) amyloid plaquesAmyloid plaque pathologyPrecursor protein processingAβ peptide levelsFocal axonal swellingsDystrophic axonsAxonal lysosomesMouse modelPeptide levelsProtein 3Lysosome accumulationLysosome transportPrimary culturesImportant regulatorPlaquesPathologyVivo importanceDisease relevance
2016
C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling
Amick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Molecular Biology Of The Cell 2016, 27: 3040-3051. PMID: 27559131, PMCID: PMC5063613, DOI: 10.1091/mbc.e16-01-0003.Peer-Reviewed Original ResearchConceptsAmino acid availabilityAcid availabilityGenome-editing strategiesKO cell linesProtein complexesSubcellular localizationKnockout phenotypesC9orf72 proteinLysosomal siteBioinformatics predictionSMCR8Tumor suppressorSwollen lysosomesFunctional interactionLysosomesC9orf72 geneCell linesStructural similarityNormal functionC9orf72PhenotypeAmyotrophic lateral sclerosisBirt-HoggIntronsMTORC1
2015
Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques
Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e3699-e3708. PMID: 26124111, PMCID: PMC4507205, DOI: 10.1073/pnas.1510329112.Peer-Reviewed Original ResearchConceptsAmyloid plaquesNeuronal lysosomesAlzheimer's diseaseAlzheimer's disease brain pathologyLysosome accumulationAlzheimer's disease (AD) amyloid plaquesΒ-amyloid depositionΒ-amyloid depositsAmyloid precursor proteinLysosome-like organellesRetrograde axonal transportWild-type brainsSuch axonsSwollen axonsMassive accumulationAxonal lysosomesBrain pathologyAmyloidogenic processingMouse modelAmyloid depositsLuminal proteasesAxonal transportLocal impairmentNeuronal processesNeurodegenerative diseases
2013
Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases
Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases. Journal Of Cell Biology 2013, 202: 1107-1122. PMID: 24081491, PMCID: PMC3787382, DOI: 10.1083/jcb.201307084.Peer-Reviewed Original ResearchMeSH KeywordsAmino AcidsBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsBlotting, WesternCarrier ProteinsCytoplasmFluorescent Antibody TechniqueHumansImmunoprecipitationLysosomesMechanistic Target of Rapamycin Complex 1Monomeric GTP-Binding ProteinsMultiprotein ComplexesProto-Oncogene ProteinsRecombinant ProteinsRNA, Small InterferingTOR Serine-Threonine KinasesTumor Suppressor ProteinsConceptsAmino acid-dependent activationAcid-dependent activationTranscription factor EBRag GTPasesSurface of lysosomesMTORC1-dependent phosphorylationAmino acid depletionLysosome recruitmentGTPase domainRAG interactionsCytoplasmic sequestrationLysosome functionGTPasesFLCNHuman diseasesFunction mutationsDevelopment of pneumothoraxProtein 1Direct interactionLysosomesCritical rolePulmonary cystsSite of actionAcid depletionFolliculin gene
2012
The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis
Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM. The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Science Signaling 2012, 5: ra42. PMID: 22692423, PMCID: PMC3437338, DOI: 10.1126/scisignal.2002790.Peer-Reviewed Original ResearchMeSH Keywords14-3-3 ProteinsAnalysis of VarianceBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsElectrophoretic Mobility Shift AssayGene Expression RegulationHeLa CellsHomeostasisHumansLysosomesMechanistic Target of Rapamycin Complex 1Microphthalmia-Associated Transcription FactorMicroscopy, ConfocalMultiprotein ComplexesMutationPhosphorylationProteinsSignal TransductionTOR Serine-Threonine KinasesConceptsMTOR-dependent phosphorylationLysosomal functionTranscription factor MITFRapamycin complex 1Transcription factor TFEBMajor cellular siteTarget of mTORTranslocation of TFEBDefective organellesTranscriptional regulationCellular needsCellular homeostasisTranscriptional controlLysosome homeostasisLysosome biogenesisTranscription factorsLysosomal biogenesisPhysiological contextRegulatory mechanismsLysosome functionMechanistic targetTFEBCellular sitesLysosomal activityBiogenesis