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
2021
Overlapping 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
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
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