2024
Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
Talaia G, Bentley-DeSousa A, Ferguson S. Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition. The EMBO Journal 2024, 43: 3948-3967. PMID: 39103493, PMCID: PMC11405869, DOI: 10.1038/s44318-024-00180-8.Peer-Reviewed Original ResearchTANK-binding kinase 1MTORC1 activityAmino acid-dependent mTORC1 activationOrganelle quality controlRegulate cell growthElevated amino acid levelsAmino acid levelsAssociated with amyotrophic lateral sclerosisIncreased mTORC1 activityCellular demandSerine 72Amino acid availabilityLysosomal homeostasisSignaling proteinsMacromolecule degradationSites of amino acidsCell growthLysosomal poolMTORC1 inhibitionKinase 1Lysosomal functionAmino acidsInnate immunityLysosomesAmyotrophic lateral sclerosis
2023
A kinesin-1 adaptor complex controls bimodal slow axonal transport of spectrin in Caenorhabditis elegans
Glomb O, Swaim G, Munoz LLancao P, Lovejoy C, Sutradhar S, Park J, Wu Y, Cason S, Holzbaur E, Hammarlund M, Howard J, Ferguson S, Gramlich M, Yogev S. A kinesin-1 adaptor complex controls bimodal slow axonal transport of spectrin in Caenorhabditis elegans. Developmental Cell 2023, 58: 1847-1863.e12. PMID: 37751746, PMCID: PMC10574138, DOI: 10.1016/j.devcel.2023.08.031.Peer-Reviewed Original ResearchLRRK2 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
Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo
Devireddy S, Ferguson SM. Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo. Journal Of Cell Biology 2021, 221: e202104044. PMID: 34919127, PMCID: PMC8689666, DOI: 10.1083/jcb.202104044.Peer-Reviewed Original ResearchTSC2 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
2020
PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s disease
Nackenoff A, Hohman T, Neuner S, Akers C, Weitzel N, Shostak A, Ferguson S, Bennett D, Schneider J, Jefferson A, Kaczorowski C, Schrag M. PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s disease. Alzheimer's & Dementia 2020, 16 DOI: 10.1002/alz.043301.Peer-Reviewed Original ResearchSporadic Alzheimer's diseaseΒ-amyloid plaquesAlzheimer's diseaseCerebral β-amyloidosisΒ-amyloid pathologyPhospholipase D3Normal human brainPre-frontal cortexAD-affected brainsFear conditioning taskReligious Orders StudyDystrophic neuritesAD brainΒ-amyloidosisMouse modelCognitive declineMouse brainPhospholipase D isoformsCognitive functionPathology severityMouse strainsDiseaseBrainRush MemoryMRNA levelsDynamin Function in Exocytosis and Endocytosis Coupling of Dense-Core Vesicles in Pancreatic Beta Cells
Fan F, Wendlick J, Tamarina N, Wu Y, Ferguson S, Philipson L, De Camilli P, Lou X. Dynamin Function in Exocytosis and Endocytosis Coupling of Dense-Core Vesicles in Pancreatic Beta Cells. Biophysical Journal 2020, 118: 488a. DOI: 10.1016/j.bpj.2019.11.2700.Peer-Reviewed Original Research
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
2018
A Novel Murine Knock‐in Model for Progranulin‐deficient Frontotemporal Dementia with Nonsense‐mediated mRNA Decay
Nguyen A, Nguyen T, Zhang J, Devireddy S, Zhou P, Karydas A, Xu X, Miller B, Rigo F, Ferguson S, Huang E, Walther T, Farese R. A Novel Murine Knock‐in Model for Progranulin‐deficient Frontotemporal Dementia with Nonsense‐mediated mRNA Decay. The FASEB Journal 2018, 32: 807.8-807.8. DOI: 10.1096/fasebj.2018.32.1_supplement.807.8.Peer-Reviewed Original ResearchFrontotemporal dementiaMRNA levelsProgranulin-deficient frontotemporal dementiaCommon neurodegenerative disorderExcessive grooming behaviorGrn knockout miceCell linesFull-text articlesSynaptic densityProgranulin deficiencyTesting therapiesGRN mutationsTherapeutic approachesKnockout miceAnimal modelsAge 60GRN mRNA levelsNeurodegenerative disordersNonsense mutationMiceProgranulin proteinText articlesNational InstituteTypes of mutationsDementia research
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
2014
Dynamin 2 regulation of integrin endocytosis, but not VEGF signaling, is crucial for developmental angiogenesis
Lee M, Skoura A, Park E, Landskroner-Eiger S, Jozsef L, Luciano A, Murata T, Pasula S, Dong Y, Bouaouina M, Calderwood D, Ferguson S, De Camilli P, Sessa W. Dynamin 2 regulation of integrin endocytosis, but not VEGF signaling, is crucial for developmental angiogenesis. Journal Of Cell Science 2014, 127: e1-e1. DOI: 10.1242/jcs.153080.Peer-Reviewed Original ResearchDynamin 2–dependent endocytosis is required for sustained S1PR1 signaling
Willinger T, Ferguson S, Pereira J, De Camilli P, Flavell R. Dynamin 2–dependent endocytosis is required for sustained S1PR1 signaling. Journal Of Cell Biology 2014, 204: 2047oia57. DOI: 10.1083/jcb.2047oia57.Peer-Reviewed Original Research
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