Featured Publications
Systems biochemistry to “deorphanize” human mitochondrial proteome
Miros F, Liu R, Shen H. Systems biochemistry to “deorphanize” human mitochondrial proteome. Molecular Cell 2022, 82: 2735-2737. PMID: 35931038, DOI: 10.1016/j.molcel.2022.07.005.Peer-Reviewed Original ResearchCombinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS
Shi X, Reinstadler B, Shah H, To TL, Byrne K, Summer L, Calvo SE, Goldberger O, Doench JG, Mootha VK, Shen H. Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS. Nature Communications 2022, 13: 2483. PMID: 35513392, PMCID: PMC9072411, DOI: 10.1038/s41467-022-30126-9.Peer-Reviewed Original ResearchConceptsDe novo purine biosynthesisMitochondrial iron uptakeStructure-guided mutagenesisNovo purine biosynthesisMetabolic stateMitochondrial glutathione transportGlutathione importGenetic interactionsGenetic perturbationsDifferent metabolic environmentsFitness defectsLack of substrateGene interactionsMitochondrial OXPHOSMitochondrial membranePurine biosynthesisCarrier familyTransport assaysKO cellsIron uptakeGlutathione transportTransport activityIron homeostasisGlutathione homeostasisGenesThe Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12
Shen H, Campanello GC, Flicker D, Grabarek Z, Hu J, Luo C, Banerjee R, Mootha VK. The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12. Cell 2017, 171: 771-782.e11. PMID: 29056341, PMCID: PMC5827971, DOI: 10.1016/j.cell.2017.09.051.Peer-Reviewed Original ResearchConceptsMethylmalonyl-CoA mutaseCitramalyl-CoA lyaseAnti-microbial metabolitesCell-autonomous defectSubstrate analogue inhibitorsMammalian cellsStructural biologyPathway assignmentItaconyl-CoAMitochondrial enzymesCellular activitiesMetabolic pathwaysDependent methylmalonyl-CoA mutaseHomozygous lossConsistent phenotypeConsequence of exposureVertebratesCellsEnzymologyBiologyMutaseLyasePhenotypeEnzymePathwayPhylogenetic Analysis Guides Transporter Protein Deorphanization: A Case Study of the SLC25 Family of Mitochondrial Metabolite Transporters.
Byrne, K.L.; Szeligowski, R.V.; Shen, H. Phylogenetic Analysis Guides Transporter Protein Deorphanization: A Case Study of the SLC25 Family of Mitochondrial Metabolite Transporters. Biomolecules 2023, 13, 1314.Peer-Reviewed Original Research
2023
Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis
Shi X, DeCiucis M, Grabinska K, Kanyo J, Liu A, Lam T, Shen H. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Molecular Cell 2023, 84: 802-810.e6. PMID: 38157846, PMCID: PMC10922821, DOI: 10.1016/j.molcel.2023.12.008.Peer-Reviewed Original ResearchProtein quality controlMitochondrial protein quality controlDual regulationMetabolic compartmentalizationIron homeostasisMitochondrial iron-sulfur clustersIron-sulfur clustersMitochondrial transportersProtein regulationMammalian cellsCRISPR knockoutCysteine residuesTransporter regulationLoop 1SLC25A39Glutathione homeostasisMetabolic sensingGlutathione uptakeMature neuronsProtein levelsHomeostasisRegulationAFG3L2Biochemical featuresMitochondrial glutathione levelsSalvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions
Skinner O, Blanco-Fernández J, Goodman R, Kawakami A, Shen H, Kemény L, Joesch-Cohen L, Rees M, Roth J, Fisher D, Mootha V, Jourdain A. Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions. Nature Metabolism 2023, 5: 765-776. PMID: 37198474, PMCID: PMC10229423, DOI: 10.1038/s42255-023-00774-2.Peer-Reviewed Original ResearchConceptsUpper glycolysisGenome-wide genetic screenNutrient-limited conditionsNon-oxidative branchGenetic screenCancer lineagesContext of diseaseRegulated stepGrowth of cellsATP productionGlyceraldehyde 3Cancer cell linesGlucose transportPrimary macrophagesGlycolysisCell linesComplete lossPyrimidine synthesisPathwayRNACarbon building blocksAlternative nutrientsRibose moietyUridineComplete absenceThe C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko N, Ahmed O, Lam T, Wang W, Shen H, Somlo S, Caplan M. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nature Communications 2023, 14: 1790. PMID: 36997516, PMCID: PMC10063565, DOI: 10.1038/s41467-023-37449-1.Peer-Reviewed Original ResearchConceptsPolycystin-1Nicotinamide nucleotide transhydrogenaseTerminal tailCystic phenotypeAutosomal dominant polycystic kidney diseaseCyst cell proliferationC-terminal domainAmino acid residuesLethal monogenic disorderC-terminal cleavageNucleotide transhydrogenaseAcid residuesMitochondrial functionTransgenic expressionPKD1 geneRedox stateShort fragmentsCell proliferationMonogenic disordersDominant polycystic kidney diseasePolycystic kidney diseaseGene therapy strategiesProteinPhenotypeFragments
2022
Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine
Moen J, Mohler K, Rogulina S, Shi X, Shen H, Rinehart J. Enhanced access to the human phosphoproteome with genetically encoded phosphothreonine. Nature Communications 2022, 13: 7226. PMID: 36433969, PMCID: PMC9700786, DOI: 10.1038/s41467-022-34980-5.Peer-Reviewed Original ResearchConceptsUbiquitous post-translational modificationCo-translational insertionKinase activation mechanismProtein interaction platformOrthogonal translation systemProtein-protein interactionsPost-translational modificationsPhospho-amino acidsAminoacyl-tRNA synthetaseHuman phosphoproteomePhosphorylation eventsTRNA pairsFunctional assignmentCellular processesProtein phosphorylationUpstream kinasePhysiological functionsActivation mechanismTranslation systemKinasePhosphorylationInteraction platformPhosphoproteomePhosphothreoninePhospho
2021
VPS13D bridges the ER to mitochondria and peroxisomes via Miro
Guillén-Samander A, Leonzino M, Hanna MG, Tang N, Shen H, De Camilli P. VPS13D bridges the ER to mitochondria and peroxisomes via Miro. Journal Of Cell Biology 2021, 220: e202010004. PMID: 33891013, PMCID: PMC8077184, DOI: 10.1083/jcb.202010004.Peer-Reviewed Original ResearchConceptsLipid transport proteinsHigher eukaryotesER-mitochondriaSecretory pathwayAccessory factorsMitochondrial dynamicsDisease pathogenesisTransport proteinsParkin substratesLipid transferSplice variantsParkinson's disease pathogenesisVps13Lipid supplyMitochondriaMiroVPS13DERMESYeastMost lipidsTransport domainEukaryotesGem1MetazoansER
2020
An IRON-clad Connection between Aging Organelles
Shen H. An IRON-clad Connection between Aging Organelles. Cell 2020, 180: 214-216. PMID: 31978339, DOI: 10.1016/j.cell.2019.12.037.Peer-Reviewed Original Research
2019
Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair
Ruetz M, Campanello GC, Purchal M, Shen H, McDevitt L, Gouda H, Wakabayashi S, Zhu J, Rubin EJ, Warncke K, Mootha VK, Koutmos M, Banerjee R. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science 2019, 366: 589-593. PMID: 31672889, PMCID: PMC7070230, DOI: 10.1126/science.aay0934.Peer-Reviewed Original ResearchMeSH KeywordsBiocatalysisCatalytic DomainCoenzyme ACrystallography, X-RayDeoxyadenosinesElectron Spin Resonance SpectroscopyHumansHydrogen BondingMacrophagesMethylmalonyl-CoA MutaseModels, MolecularMycobacterium tuberculosisPropionatesProtein ConformationProtein MultimerizationProtein SubunitsSuccinatesVitamin B 12Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
Wang LW, Shen H, Nobre L, Ersing I, Paulo JA, Trudeau S, Wang Z, Smith NA, Ma Y, Reinstadler B, Nomburg J, Sommermann T, Cahir-McFarland E, Gygi SP, Mootha VK, Weekes MP, Gewurz BE. Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation. Cell Metabolism 2019, 30: 539-555.e11. PMID: 31257153, PMCID: PMC6720460, DOI: 10.1016/j.cmet.2019.06.003.Peer-Reviewed Original ResearchMeSH KeywordsAminohydrolasesB-LymphocytesCell Transformation, ViralEpstein-Barr Virus InfectionsEpstein-Barr Virus Nuclear AntigensFemaleFolic AcidGlycolysisHEK293 CellsHerpesvirus 4, HumanHumansLymphocyte ActivationMethylenetetrahydrofolate Dehydrogenase (NADP)MitochondriaMultifunctional EnzymesNADPOxidation-ReductionProteomeProto-Oncogene Proteins c-mycSerineConceptsEpstein-Barr virusOne-carbon metabolismSynthesis of serinePost-transplant B cell lymphomasB-cell transformationPrimary human B cellsMitochondrial remodelingTargets MYCRedox defenseNADPH productionB-cell outgrowthCell transformationMetabolic pathwaysB-cell lymphomaPotential therapeutic targetB cell growthMitochondrial NADPHViral proteinsB cell proliferationCell growthNADPH levelsHuman B cellsCell proliferationMTHFD2Infected cells
2017
A genetically encoded tool for manipulation of NADP+/NADPH in living cells
Cracan V, Titov DV, Shen H, Grabarek Z, Mootha VK. A genetically encoded tool for manipulation of NADP+/NADPH in living cells. Nature Chemical Biology 2017, 13: 1088-1095. PMID: 28805804, PMCID: PMC5605434, DOI: 10.1038/nchembio.2454.Peer-Reviewed Original ResearchComparative Analysis of Mitochondrial N-Termini from Mouse, Human, and Yeast*
Calvo SE, Julien O, Clauser KR, Shen H, Kamer KJ, Wells JA, Mootha VK. Comparative Analysis of Mitochondrial N-Termini from Mouse, Human, and Yeast*. Molecular & Cellular Proteomics 2017, 16: 512-523. PMID: 28122942, PMCID: PMC5383775, DOI: 10.1074/mcp.m116.063818.Peer-Reviewed Original ResearchConceptsN-terminusMitochondrial proteinsCleavage eventsMature mitochondrial proteinN-terminal presequenceNovel protein isoformsN-end ruleAmino acidsMultiple cleavage eventsMitochondrial processingNuclear genomeHuman U937 cellsMature proteinMitochondrial peptidasesYeast proteinsProtein isoformsSequence levelCanonical motifsIndividual proteinsPresequenceDistinct enzymesPolypeptide cleavageCleavage siteYeastProtein
2014
Coupling between endocytosis and sphingosine kinase 1 recruitment
Shen H, Giordano F, Wu Y, Chan J, Zhu C, Milosevic I, Wu X, Yao K, Chen B, Baumgart T, Sieburth D, De Camilli P. Coupling between endocytosis and sphingosine kinase 1 recruitment. Nature Cell Biology 2014, 16: 652-662. PMID: 24929359, PMCID: PMC4230894, DOI: 10.1038/ncb2987.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCaenorhabditisCell MembraneCells, CulturedChlorocebus aethiopsCholesterolCOS CellsEndocytosisFluorescent Antibody TechniqueHEK293 CellsHeLa CellsHumansMiceModels, MolecularMutationPhosphotransferases (Alcohol Group Acceptor)Protein BindingProtein Structure, TertiarySequence AnalysisConceptsSphingosine kinase 1Hydrophobic patchN-BAR proteinsEndocytic membrane trafficExo/endocytosisPlasma membrane resultsMembrane trafficEndocytic intermediatesFunction mutantsMembrane recruitmentEndocytic membranesCellular compartmentsIntercellular signalingRecycling defectsSphingosine phosphorylationKinase 1Genetic studiesFunctional linkTubular invaginationsSphingolipid metabolismLipid bilayersEndocytosisEnzyme surfaceMembrane resultsRecruitmentA Novel Multiple Hypothesis Based Particle Tracking Method for Clathrin Mediated Endocytosis Analysis Using Fluorescence Microscopy
Liang L, Shen H, De Camilli P, Duncan JS. A Novel Multiple Hypothesis Based Particle Tracking Method for Clathrin Mediated Endocytosis Analysis Using Fluorescence Microscopy. IEEE Transactions On Image Processing 2014, 23: 1844-1857. PMID: 24808351, PMCID: PMC4373089, DOI: 10.1109/tip.2014.2303633.Peer-Reviewed Original Research
2013
Dynamin triple knockout cells reveal off target effects of commonly used dynamin inhibitors
Park RJ, Shen H, Liu L, Liu X, Ferguson SM, De Camilli P. Dynamin triple knockout cells reveal off target effects of commonly used dynamin inhibitors. Journal Of Cell Science 2013, 126: 5305-5312. PMID: 24046449, PMCID: PMC3828596, DOI: 10.1242/jcs.138578.Peer-Reviewed Original ResearchConceptsDynamin 1Dynamin inhibitorTKO cellsPeripheral membrane rufflingDouble knockoutDynamin 3 geneClathrin-mediated endocytosisTriple-knockout cellsDynamin-dependent processFluid-phase endocytosisDyngo-4aMembrane fissionMembrane rufflingDKO cellsDynamin 2Knockout cellsLow-level expressionCell physiologyDynaminEndocytosisTarget effectsDKO fibroblastsGenesCellsKO fibroblastsA Multiple Hypothesis Based Method for Particle Tracking and Its Extension for Cell Segmentation
Liang L, Shen H, Rompolas P, Greco V, De Camilli P, Duncan JS. A Multiple Hypothesis Based Method for Particle Tracking and Its Extension for Cell Segmentation. Lecture Notes In Computer Science 2013, 23: 98-109. PMID: 24683961, PMCID: PMC4122512, DOI: 10.1007/978-3-642-38868-2_9.Peer-Reviewed Original Research
2012
SnapShot: Membrane Curvature Sensors and Generators
Shen H, Pirruccello M, De Camilli P. SnapShot: Membrane Curvature Sensors and Generators. Cell 2012, 150: 1300-1300.e2. PMID: 22980986, PMCID: PMC3819217, DOI: 10.1016/j.cell.2012.08.017.Peer-Reviewed Original ResearchA BAYESIAN METHOD FOR 3D ESTIMATION OF SUBCELLULAR PARTICLE FEATURES IN MULTI-ANGLE TIRF MICROSCOPY
Liang L, Shen H, Xu Y, De Camilli P, Toomre D, Duncan J. A BAYESIAN METHOD FOR 3D ESTIMATION OF SUBCELLULAR PARTICLE FEATURES IN MULTI-ANGLE TIRF MICROSCOPY. 2012, 1: 984-987. DOI: 10.1109/isbi.2012.6235722.Peer-Reviewed Original Research